PGDH inhibitors and methods of making and using

ABSTRACT

Disclosed herein are compounds that can inhibit 15-hydroxyprostaglandin dehydrogenase. Such compounds may be administered to subjects that may benefit from modulation of prostaglandin levels.

This application is a continuation of U.S. application Ser. No.17/484,398, filed Sep. 24, 2021, which is a continuation of PCTInternational Application No. PCT/US2021/014783, filed Jan. 22, 2021,which claims the benefit of U.S. Provisional Application No. 62/965,062,filed Jan. 23, 2020; U.S. Provisional Application No. 63/007,755, filedApr. 9, 2020; U.S. Provisional Application No. 63/029,184, filed May 22,2020; U.S. Provisional Application No. 63/092,116, filed Oct. 15, 2020;U.S. Provisional Application No. 63/110,803, filed Nov. 6, 2020; andU.S. Provisional Application No. 63/133,965, filed Jan. 5, 2021, each ofwhich is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Prostaglandins are a group of physiologically active lipid compoundswith diverse biological effects including vasodilation, inhibition ofplatelet aggregation, bronchodilation, bronchoconstriction, immuneresponses, contraction and relaxation of gastrointestinal smoothmuscles, gastric acid secretion, gastric mucus secretion, uteruscontraction, lipolysis inhibition, neurotransmission, clotting,hyperalgesia, and pyrexia.

Treatment of diseases or disorders may require activation ofprostaglandins, or inhibition of inactivation of prostaglandins.Hydroxyprostaglandin dehydrogenases, such as 15-hydroxyprostaglandindehydrogenase (15-PGDH) are involved in the inactivation ofprostaglandins. As such, diseases/disorders associated withprostaglandins can be prevented, treated and/or managed using inhibitorsof hydroxyprostaglandin dehydrogenase such as inhibitors of 15-PGDH.

SUMMARY OF THE INVENTION

In one aspect, provided herein is a method of inhibiting15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is selected from —OCH₂—, —C(O)NH—, —NHC(O)—, —C(O)NMe-,        —NMeC(O)—, —SCH₂—, —S(O)CH₂—, —SO₂CH₂—;    -   each Y is independently selected from N and CR¹¹;    -   each R¹ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo or thio;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   each R⁵ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁸ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; each R¹¹ is independently        selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,        —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,        —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to        10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl;    -   n is 0, 1, 2, 3, 4, or 5;    -   m is 0, 1, 2, 3, or 4; and    -   p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;    -   provided that the compound of Formula I is not

In some embodiments, the compound is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of inhibiting15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   T, U, W, X, and Y are independently selected from N and CR⁵;    -   S, V, and Z are independently selected from N and C;    -   R¹ is selected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;        wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally        substituted with 1 to 3 substituents independently selected from        halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,        —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,        —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo or thio;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or    -   two R⁴'s are taken together with the carbon atoms to which they        are attached and any intervening atoms to form a        C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently        selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷,        —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,        —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,        C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   each R⁵ is independently selected from H, halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆ heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁸ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; and    -   n is 1, 2, 3, or 4; and    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;    -   provided that the compound of Formula II is not

In some embodiments, the compound is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

In some embodiments, the compound is a compound of Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

In some embodiments, the compound is a compound of Formula IIc:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,4, or 5.

In some embodiments, the compound is a compound of Formula IId:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, the compound is a compound of Formula IIe:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, the compound is a compound of Formula IIf:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, the compound is a compound of Formula IIg:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, the compound is a compound of Formula IIh:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, the compound is a compound of Formula IIi:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, the compound is a compound of Formula IIj:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, the compound is a compound of Formula IIn:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, the compound is a compound of Formula IIp:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In another aspect, provided herein is a method of inhibiting15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each X is independently selected from N and CR⁷;    -   Y is selected from O, S, SO₂, and C(R⁸)₂;    -   R¹ is selected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;        wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally        substituted with 1 to 3 substituents independently selected from        halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,        —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo or thio;    -   R⁴ and R⁵ are independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; wherein        each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is        independently optionally substituted with 1 to 3 substituents        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or    -   R⁴ and R⁵ are taken together, along with the nitrogen atom to        which they are attached, to form a 3-to 10-membered        heterocycloalkyl optionally substituted with 1 to 3 substituents        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   each R⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or    -   two R⁶'s attached to the same carbon atom are taken together to        form oxo, thio, or C₃₋₁₀cycloalkyl, and any remaining R⁶'s are        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   each R⁷ is independently selected from H, halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   each R⁸ is independently selected from H, halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or    -   two R⁸'s can be taken together to form a C₃₋₁₀cycloalkyl        optionally substituted with 1 to 3 substituents independently        selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,        —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,        —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to        10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl;    -   R⁹ and R¹⁰ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹² is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   m is 1 or 2; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, the compound is a compound of Formula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R¹⁴ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; and    -   p is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IIId:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R¹⁴ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; and    -   p is 0, 1, 2, or 3.

In another aspect, provided herein is a compound of Formula IIk:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   T, U, and Y are independently selected from N and CR⁶, provided        that when U is N, at least one of T and Y is N;    -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein the aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁷R⁸,        —OR⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸,        —NR¹¹C(O)R⁹, —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹SO₂NR⁷R⁸,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and        5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   each R⁴ is independently selected from H and halo;    -   R⁵ is selected from halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹,        —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹.        —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹SO₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R⁶ is selected from H, halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹,        —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,        —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹SO₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R⁷ and R⁸ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl;    -   each R⁹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹¹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₆cycloalkyl; and    -   p is 0, 1, or 2.

In another aspect, provided herein is a compound of Formula IIm:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein said aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁶R⁷,        —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and        5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆ heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; or    -   two R⁴'s are taken together with the carbon atoms to which they        are attached and any intervening atoms to form a        C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently        selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷,        —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,        —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,        C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl;    -   R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,        —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,        —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₁₋₆aryl, and 5- to 10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁸ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   p is 0, 1, 2, or 3.

In another aspect, provided herein is a compound of Formula IIq:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein said aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁶R⁷,        —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and        5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; or    -   two R⁴'s are taken together with the carbon atoms to which they        are attached and any intervening atoms to form a        C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently        selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷,        —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,        —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,        C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl;    -   R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,        —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,        —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁸ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   p is 0, 1, 2, or 3.

In another aspect, provided herein is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each X is independently selected from N and CR⁷;    -   Y is selected from O, S, SO₂, and C(R⁸)₂;    -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein the aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁹R¹⁰,        —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,        —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,        C₃₋₆cycloalkyl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   R⁴ and R⁵ are independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₆cycloalkyl; wherein each        alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently        optionally substituted with 1 to 3 substituents independently        selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,        —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,        —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;        or    -   R⁴ and R⁵ are taken together, along with the nitrogen atom to        which they are attached, to form a 3- to 10-membered        heterocycloalkyl optionally substituted with 1 to 3 substituents        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆        alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   each R⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₁₋₆cycloalkyl, 3- to        10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl; or    -   two R⁶'s attached to the same carbon atom are taken together to        form oxo, and any remaining R⁶'s are independently selected from        halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,        —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₆cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl,        and 5- to 10-membered heteroaryl;    -   each R⁷ and R⁸ is independently selected from halo, —NR⁹R¹⁰,        —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,        —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,        C₃₋₆cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl,        and 5- to 10-membered heteroaryl;    -   R⁹ and R¹⁰ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl;    -   each R¹¹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹² is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₆cycloalkyl; and    -   n is 0, 1, 2, 3, or 4.

In another aspect, provided herein is a composition comprising acompound selected from the group consisting of:

In another aspect, provided herein is a composition comprising acompound selected from the group consisting of:

In another aspect, provided herein is a composition comprising acompound selected from the group consisting of:

In another aspect, provided herein is a method of promoting and/orstimulation skin pigmentation, comprising administering one or more ofthe compositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of inhibiting hair loss,comprising administering one or more of the compositions describedherein to a subject in need thereof.

method of preventing and/or treating skin inflammation and/or damage,comprising administering one or more of the compositions describedherein to a subject in need thereof.

In another aspect, provided herein is a method of preventing and/ortreating vascular insufficiency, comprising administering one or more ofthe compositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of preventing, treating,minimizing and/or reversing congestive heart failure, cardiomyopathy,comprising administering one or more of the compositions describedherein to a subject in need thereof.

In another aspect, provided herein is a method of reducing cardiacejection fraction, comprising administering one or more of thecompositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of preventing and/ortreating a gastrointestinal disease, comprising administering one ormore of the compositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of preventing and/ortreating renal dysfunction, comprising administering one or more of thecompositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of stimulation boneresorption and bone formation, comprising administering one or more ofthe compositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of stimulating tissueregeneration by stimulating, comprising administering one or more of thecompositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of modulating cervicalripening, comprising administering one or more of the compositionsdescribed herein to a subject in need thereof.

In another aspect, provided herein is a method of promotingneuroprotection and/or stimulating neuronal regeneration, comprisingadministering one or more of the compositions described herein to asubject in need thereof.

In another aspect, provided herein is a method of treating and/orpreventing a neurological disorder, a neuropsychiatric disorder, aneural injury, a neural toxicity disorder, a neuropathic pain, or aneural degenerative disorder, comprising administering one or more ofthe compositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of treating and/orpreventing fibrotic or adhesion disease, disorder or condition,comprising administering one or more of the compositions describedherein to a subject in need thereof.

In another aspect, provided herein is a method of reducing and/orpreventing scar formation, comprising administering one or more of thecompositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of treating and/orpreventing muscle disorder, muscle injury and/or muscle atrophy,comprising administering one or more of the compositions describedherein to a subject in need thereof.

In another aspect, provided herein is a method of treating and/orpreventing fibrosis, comprising administering one or more of thecompositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of treating and/orpreventing idiopathic pulmonary fibrosis, comprising administering oneor more of the compositions described herein to a subject in needthereof.

In another aspect, provided herein is a method of treating and/orpreventing kidney fibrosis, comprising administering one or more of thecompositions described herein to a subject in need thereof.

In another aspect, provided herein is a method of stimulating muscleregeneration, comprising administering one or more of said compositionsdescribed herein to a subject in need thereof.

In another aspect, provided herein is a method of promoting organfitness, comprising administering one or more of said compositionsdescribed herein to a subject in need thereof.

In another aspect, provided herein is a method of promoting woundhealing, comprising administering one or more of said compositionsdescribed herein to a subject in need thereof.

In another aspect, provided herein is a method of treating acute kidneyinjury, comprising administering one or more of said compositionsdescribed herein to a subject in need thereof.

In another aspect, provided herein is a method of treating sarcopenia,comprising administering one or more of said compositions describedherein to a subject in need thereof.

In another aspect, provided herein is a method of treating aneuromuscular disease, comprising administering one or more of saidcompositions of any of the preceding claims to a subject in needthereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. An understanding of the features and advantages ofthe present invention may be obtained by reference to the followingdetailed description that sets forth illustrative embodiments, in whichthe principles of the invention are utilized, and the accompanyingdrawings of which:

FIG. 1 shows results of the cell-based assay for exemplary compounds.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this disclosure belongs.

As used herein, the singular form “a”, “an” and “the” includes pluralreferences unless the context clearly dictates otherwise.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas alkyl, haloalkyl, or heteroalkyl, is meant to include groups thatcontain from x to y carbons in the chain. For example, the term“C₁₋₆alkyl” refers to substituted or unsubstituted saturated hydrocarbongroups, including straight-chain alkyl and branched-chain alkyl groupsthat contain from 1 to 6 carbons. The term —C_(x-y)alkylene- refers to asubstituted or unsubstituted alkylene chain with from x to y carbons inthe alkylene chain. For example —C₁₋₆alkylene- may be selected frommethylene, ethylene, propylene, butylene, pentylene, and hexylene, anyone of which is optionally substituted.

“Alkyl” refers to substituted or unsubstituted saturated hydrocarbongroups, including straight-chain alkyl and branched-chain alkyl groups.An alkyl group may contain from one to twelve carbon atoms (e.g., C₁₋₁₂alkyl), such as one to eight carbon atoms (C₁₋₈ alkyl) or one to sixcarbon atoms (C₁₋₆ alkyl). Exemplary alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkylgroup is attached to the rest of the molecule by a single bond. Unlessstated otherwise specifically in the specification, an alkyl group isoptionally substituted by one or more substituents such as thosesubstituents described herein.

“Haloalkyl” refers to an alkyl group that is substituted by one or morehalogens. Exemplary haloalkyl groups include trifluoromethyl,difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

“Heteroalkyl” refers to a substituted or unsubstituted alkyl group whichhas one or more skeletal chain atoms selected from an atom other thancarbon. Exemplary skeletal chain atoms selected from an atom other thancarbon include, e.g., O, N, P, Si, S, or combinations thereof, whereinthe nitrogen, phosphorus, and sulfur atoms may optionally be oxidizedand the nitrogen heteroatom may optionally be quaternized. If given, anumerical range refers to the chain length in total. For example, a 3-to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connectionto the rest of the molecule may be through either a heteroatom or acarbon in the heteroalkyl chain. Unless stated otherwise specifically inthe specification, a heteroalkyl group is optionally substituted by oneor more substituents such as those substituents described herein.

“Aryl” refers to an aromatic ring wherein each of the atoms forming thering is a carbon atom. Aryl groups can be optionally substituted.Examples of aryl groups include, but are not limited to, phenyl andnaphthyl. In some embodiments, the aryl is phenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group). Unless stated otherwise specifically in thespecification, the term “aryl” or the prefix “ar-” (such as in“aralkyl”) is meant to include aryl radicals that are optionallysubstituted.

“Heteroaryl” refers to a 3- to 12-membered aromatic ring that comprisesat least one heteroatom wherein each heteroatom may be independentlyselected from N, O, and S. As used herein, the heteroaryl ring may beselected from monocyclic or bicyclic and fused or bridged ring systemswherein at least one of the rings in the ring system is aromatic, i.e.,it contains a cyclic, delocalized (4n+2) π-electron system in accordancewith the Hückel theory. The heteroatom(s) in the heteroaryl may beoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the heteroaryl, valence permitting,such as a carbon or nitrogen atom of the heteroaryl. Examples ofheteroaryls include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[b]quinazolinyl, 5,6-dihydrobenzo[b]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[b]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteroaryl is optionally substituted by one or more substituents such asthose substituents described herein.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. In some embodiments, cycloalkyls are saturatedor partially unsaturated. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls arefused with an aromatic ring (in which case the cycloalkyl is bondedthrough a non-aromatic ring carbon atom). Cycloalkyl groups includegroups having from 3 to 10 ring atoms. Representative cycloalkylsinclude, but are not limited to, cycloalkyls having from three to tencarbon atoms, from three to eight carbon atoms, from three to six carbonatoms, or from three to five carbon atoms. Monocyclic cycloalkylradicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include,for example, adamantyl, 1,2-dihydronaphthalenyl,1,4-dihydronaphthalenyl, tetrainyl, decalinyl,3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl andbicycle[1.1.1]pentyl. Unless otherwise stated specifically in thespecification, a cycloalkyl group may be optionally substituted.

The term “heterocycloalkyl” refers to a cycloalkyl group that includesat least one heteroatom selected from nitrogen, oxygen, and sulfur.Unless stated otherwise specifically in the specification, theheterocycloalkyl radical may be a monocyclic, or bicyclic ring system,which may include fused (when fused with an aryl or a heteroaryl ring,the heterocycloalkyl is bonded through a non-aromatic ring atom) orbridged ring systems. The nitrogen, carbon or sulfur atoms in theheterocyclyl radical maybe optionally oxidized. The nitrogen atom may beoptionally quaternized. The heterocycloalkyl radical may be partially orfully saturated. Examples of heterocycloalkyl radicals include, but arenot limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl,tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes allring forms of carbohydrates, including but not limited tomonosaccharides, disaccharides and oligosaccharides. Unless otherwisenoted, heterocycloalkyls have from 2 to 12 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl group may be optionally substituted.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or heteroatoms of the structure. Itwill be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms.Substituents can include any substituents described herein, for example,an oxo, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, aheterocycloalkyl, an aromatic and heteroaromatic moiety.

It will be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to a“heteroaryl” group or moiety implicitly includes both substituted andunsubstituted variants.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl group may or may not be substituted and that the descriptionincludes both substituted aryl groups and aryl groups having nosubstitution.

Compounds of the present disclosure also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantlyfound in nature. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are encompassed within the scopeof the present disclosure. For example, hydrogen has three naturallyoccurring isotopes, denoted ¹H (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope of hydrogen in nature.Enriching for deuterium may afford certain therapeutic advantages, suchas increased in vivo half-life and/or exposure, or may provide acompound useful for investigating in vivo routes of drug elimination andmetabolism. Isotopically-enriched compounds may be prepared byconventional techniques well known to those skilled in the art.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” or“diastereomers” are stereoisomers that have at least two asymmetricatoms but are not mirror images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer, the stereochemistry ateach chiral carbon can be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) in which theyrotate plane polarized light at the wavelength of the sodium D line.Certain compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms, the asymmetric centers of which can be defined, interms of absolute stereochemistry, as (R)- or (S)-. The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible stereoisomers, including racemic mixtures, opticallypure forms, mixtures of diastereomers and intermediate mixtures.Optically active (R)- and (S)-isomers can be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.The optical activity of a compound can be analyzed via any suitablemethod, including but not limited to chiral chromatography andpolarimetry, and the degree of predominance of one stereoisomer over theother isomer can be determined.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E-form (or cis- or trans-form).Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, chemical entities described hereinare intended to include all Z-, E- and tautomeric forms as well.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation procedurescan be had by reference to the examples herein below. However, otherequivalent separation or isolation procedures can also be used.

When stereochemistry is not specified, certain small molecules describedherein include, but are not limited to, when possible, their isomers,such as enantiomers and diastereomers, mixtures of enantiomers,including racemates, mixtures of diastereomers, and other mixturesthereof, to the extent they can be made by one of ordinary skill in theart by routine experimentation. In those situations, the singleenantiomers or diastereomers, i.e., optically active forms, can beobtained by asymmetric synthesis or by resolution of the racemates ormixtures of diastereomers. Resolution of the racemates or mixtures ofdiastereomers, if possible, can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example, a chiralhigh-pressure liquid chromatography (HPLC) column. Furthermore, amixture of two enantiomers enriched in one of the two can be purified toprovide further optically enriched form of the major enantiomer byrecrystallization and/or trituration. In addition, such certain smallmolecules include Z- and E-forms (or cis- and trans-forms) of certainsmall molecules with carbon-carbon double bonds or carbon-nitrogendouble bonds. Where certain small molecules described herein exist invarious tautomeric forms, the term “certain small molecule” is intendedto include all tautomeric forms of the certain small molecule.

The term “salt” or “pharmaceutically acceptable salt” refers to saltsderived from a variety of organic and inorganic counter ions well knownin the art. Pharmaceutically acceptable acid addition salts can beformed with inorganic acids and organic acids. Inorganic acids fromwhich salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Organic bases from which salts can be derivedinclude, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

The phrase “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier” as used herein means a pharmaceutically acceptablematerial, composition or vehicle, such as a liquid or solid filler,diluent, excipient, solvent or encapsulating material. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Someexamples of materials which can serve as pharmaceutically acceptablecarriers include: (1) sugars, such as lactose, glucose and sucrose; (2)starches, such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar, (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toaffect the intended application, including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended treatment application (in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that mayinduce a particular response in target cells, e.g., reduction ofplatelet adhesion and/or cell migration. The specific dose may varydepending on the particular compounds chosen, the dosing regimen to befollowed, whether it is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which it is carried.

As used herein, “treatment” or “treating” refers to an approach forobtaining beneficial or desired results with respect to a disease,disorder, or medical condition including but not limited to atherapeutic benefit and/or a prophylactic benefit. A therapeutic benefitcan include, for example, the eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit caninclude, for example, the eradication or amelioration of one or more ofthe physiological symptoms associated with the underlying disorder suchthat an improvement is observed in the subject, notwithstanding that thesubject may still be afflicted with the underlying disorder. In certainembodiments, for prophylactic benefit, the compositions are administeredto a subject at risk of developing a particular disease, or to a subjectreporting one or more of the physiological symptoms of a disease, eventhough a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal, including humans, so that bothagents and/or their metabolites are present in the subject at the sametime. Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction (e.g., activity, expression, binding, protein-proteininteraction) of a target protein or enzyme. Accordingly, the terms“antagonist” and “inhibitor” are defined in the context of thebiological role of the target protein. While preferred antagonistsherein specifically interact with (e.g., bind to) the target, compoundsthat inhibit a biological activity of the target protein by interactingwith other members of the signal transduction pathway of which thetarget protein is a member are also specifically included within thisdefinition. A preferred biological activity inhibited by an antagonistis associated with the development, growth, or spread of a tumor.

Whenever a protein is referred to herein, it will be understood that asingle protein can be referred to by different names. For example,“15-PGDH”, “PGDH”, and “hPGDH” all refer to the same protein,15-hydroxyprostaglandin dehydrogenase.

Methods of Inhibiting 15-PGDH

Provided herein are methods of inhibiting 15-hydroxyprostaglandindehydrogenase (15-PGDH).

In one aspect, provided herein is a method of inhibiting15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is selected from —OCH₂—, —C(O)NH—, —NHC(O)—, —C(O)NMe-,        —NMeC(O)—, —SCH₂, —S(O)CH₂—, —SO₂CH₂—;    -   each Y is independently selected from N and CR¹¹;    -   each R¹ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆-heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo or thio;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₆₋₁₀haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   each R⁵ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁹, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁸ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R¹¹ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   n is 0, 1, 2, 3, 4, or 5;    -   m is 0, 1, 2, 3, or 4; and    -   p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;    -   provided that the compound of Formula I is not

In some embodiments, X is selected from —OCH₂—, —C(O)NH—, —NHC(O)—,—C(O)NMe-, —NMeC(O)—, —SCH₂—, —S(O)CH₂—, and —SO₂CH₂—. In someembodiments, X is —OCH₂—. In some embodiments, X is —C(O)NH—. In someembodiments, X is —NHC(O)—. In some embodiments, X is —C(O)NMe-. In someembodiments, X is —NMeC(O)—. In some embodiments, X is —SCH₂—. In someembodiments, X is —S(O)CH₂—. In some embodiments, X is —SO₂CH₂—.

In some embodiments, each Y is independently selected from N and CR¹¹.In some embodiments, each Y is N. In some embodiments, each Y is CR¹¹.In some embodiments, one Y is N and the other Y is CR¹¹.

In some embodiments, each R¹ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R¹ is independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and—NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R¹ is independently selectedfrom halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, eachR¹ is independently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, and—C(O)OR⁸.

In some embodiments, R² is H and R³ is —CF₃. In some embodiments, R² andR³ are taken together to form oxo. In some embodiments, R² and R³ aretaken together to form thio.

In some embodiments, each R⁴ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, eachR⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷.In some embodiments, each R⁴ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, and —C(O)OR⁸.

In some embodiments, each R⁵ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, each R⁵ is independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, eachR⁵ is independently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁹,—C(O)NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷.In some embodiments, each R⁵ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, and —C(O)OR⁸.

In some embodiments, R⁶ and R⁷ are independently selected at eachoccurrence from H, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, R⁶ and R⁷ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R⁶ and R⁷ are independently selectedat each occurrence from H, and C₁₋₆alkyl.

In some embodiments, each R⁸ is independently selected from H,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ isindependently selected from H, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, each R⁸ isindependently selected from H, C₁₋₆alkyl, C₁₋₆ heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R⁸ is independently selectedfrom H, and C₁₋₆alkyl.

In some embodiments, each R⁹ is independently selected from C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R⁹ is independentlyselected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, each R⁹ is independently selectedfrom C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments,each R⁹ is independently selected from C₁₋₆alkyl.

In some embodiments, each R¹⁰ is independently selected from H,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, eachR¹⁰ is independently selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl. Insome embodiments, each R¹⁰ is independently selected from H andC₁₋₆alkyl.

In some embodiments, each R¹¹ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, each R¹¹ is independently selected from halo, —NR⁶R⁷,—OR¹¹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In someembodiments, each R¹¹ is independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R¹¹ is independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, and —C(O)OR⁸.

In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is0. In some embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3. In some embodiments, n is 4. In some embodiments, nis 5.

In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0.In some embodiments, m is 1. In some embodiments, m is 2. In someembodiments, m is 3. In some embodiments, m is 4.

In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, p is 0. In some embodiments, p is 1. In some embodiments, pis 2. In some embodiments, p is 3. In some embodiments, p is 4. In someembodiments, p is 5. In some embodiments, p is 6. In some embodiments, pis 7. In some embodiments, p is 8. In some embodiments, p is 9. In someembodiments, p is 10.

In some embodiments, the compound is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of inhibiting15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   T, U, W, X, and Y are independently selected from N and CR⁵;    -   S, V, and Z are independently selected from N and C;    -   R¹ is selected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;        wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally        substituted with 1 to 3 substituents independently selected from        halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,        —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,        —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo or thio;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or    -   two R⁴'s are taken together with the carbon atoms to which they        are attached and any intervening atoms to form a        C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently        selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷,        —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,        —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,        C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   each R⁵ is independently selected from H, halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; and    -   n is 1, 2, 3, or 4; and    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;    -   provided that the compound of Formula II is not

In some embodiments, T, U, W, X, and Y are independently selected from Nand CR⁵. In some embodiments, at least one of T, U, W, X, and Y is N andthe rest are CR⁵. In some embodiments, at least two of T, U, W, X, and Yare N and the rest are CR⁵. In some embodiments, at least three of T, U,W, X, and Y are N and the rest are CR⁵. In some embodiments, at leastfour of T, U, W, X, and Y are N and the rest are CR⁵. In someembodiments, T, U, W, X, and Y are CR⁵. In some embodiments, T, U, W, X,and Y are N.

In some embodiments, S, V, and Z are independently selected from N andC. In some embodiments, at least one of S, V, and Z is N and the restare C. In some embodiments, at least two of S, V, and Z are N and therest are C. In some embodiments, S, V, and Z are N. In some embodiments,S, V, and Z are C.

In some embodiments, R¹ is selected from C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and 5- to10-membered heteroaryl. In some embodiments, R¹ is selected fromC₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl; wherein the alkyl, aryl, or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and 5- to10-membered heteroaryl. In some embodiments, R¹ is selected fromC₆₋₁₀aryl and 5- to 10-membered heteroaryl; wherein the aryl orheteroaryl is optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,—NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments,R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl; whereinthe aryl or heteroaryl is optionally substituted with 1 to 3substituents independently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, R¹is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl; wherein thearyl or heteroaryl is optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, and—C(O)NR⁶R⁷.

In some embodiments, R² is H and R³ is —CF₃. In some embodiments, R² andR³ are taken together to form oxo. In some embodiments, R² and R³ aretaken together to form thio.

In some embodiments, each R⁴ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁹, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆ alkyl, C₁₋₆heteroalkyl,and C₁₋₆haloalkyl. In some embodiments, each R⁴ is independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and—NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁴ is independently selectedfrom halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷. In someembodiments, each R⁴ is halo. In some embodiments, each R⁴ is fluoro.

In some embodiments, two R⁴'s are taken together with the carbon atomsto which they are attached and any intervening atoms to form aC₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently selected fromhalo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl. In some embodiments, two R⁴'s are taken together with thecarbon atoms to which they are attached and any intervening atoms toform a C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,—NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, two R⁴'s are taken together with the carbon atoms to whichthey are attached and any intervening atoms to form a C₃₋₁₀cycloalkyl,and any remaining R⁴'s are independently selected from halo, —NR⁶R⁷,—OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In someembodiments, two R⁴'s are taken together with the carbon atoms to whichthey are attached and any intervening atoms to form a C₃₋₁₀cycloalkyl,and any remaining R⁴'s are independently selected from halo, —NR⁶R⁷,—OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷. In some embodiments, two R⁴'sare taken together with the carbon atoms to which they are attached andany intervening atoms to form a C₃₋₁₀cycloalkyl, and any remaining R⁴'sare independently selected from halo. In some embodiments, two R⁴'s aretaken together with the carbon atoms to which they are attached and anyintervening atoms to form a C₃₋₁₀cycloalkyl, and any remaining R⁴'s arefluoro.

In some embodiments, each R⁵ is independently selected from H, halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, each R⁵ is independently selected from H, halo, —NR⁶R⁷,—OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆ alkyl,C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, each R⁵ isindependently selected from H, halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,—NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁵ isindependently selected from H, halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,and —C(O)NR⁶R⁷.

In some embodiments, each R⁵ is independently selected from H and halo.

In some embodiments, R⁶ and R⁷ are independently selected at eachoccurrence from H, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, R⁶ and R⁷ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R⁶ and R⁷ are independently selectedat each occurrence from H and C₁₋₆alkyl.

In some embodiments, each R⁸ is independently selected from H,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ isindependently selected from H, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, each R⁸ isindependently selected from H, C₁₋₆alkyl, C₁₋₆ heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R⁸ is independently selectedfrom H and C₁₋₆ alkyl.

In some embodiments, each R⁹ is independently selected from C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R⁹ is independentlyselected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, each R⁹ is independently selectedfrom C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆ haloalkyl. In someembodiments, each R⁹ is independently selected from C₁₋₆alkyl.

In some embodiments, each R¹⁰ is independently selected from H,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, eachR¹⁰ is independently selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl. Insome embodiments, each R¹⁰ is independently selected from H andC₁₋₆alkyl.

In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. Insome embodiments, n is 2. In some embodiments, n is 3. In someembodiments, n is 4.

In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, m is 0. In some embodiments, m is 1. In some embodiments, mis 2. In some embodiments, m is 3. In some embodiments, m is 4. In someembodiments, m is 5. In some embodiments, m is 6. In some embodiments, mis 7. In some embodiments, m is 8. In some embodiments, m is 9. In someembodiments, m is 10.

In some embodiments, the compound is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2.

In some embodiments, the compound is a compound of Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2.

In some embodiments, the compound is a compound of Formula IIc:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,4, or 5.

In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is0. In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4. In some embodiments, pis 5.

In some embodiments, the compound is a compound of Formula IId:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0.In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4.

In some embodiments, the compound is a compound of Formula IIe:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0.In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4.

In some embodiments, the compound is a compound of Formula IIf:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In some embodiments, the compound is a compound of Formula IIg:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0.In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4.

In some embodiments, the compound is a compound of Formula IIh:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In some embodiments, the compound is a compound of Formula IIi:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0.In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4.

In some embodiments, the compound is a compound of Formula IIj:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In some embodiments, the compound is a compound of Formula IIn:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or3.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In some embodiments, the compound is a compound of Formula IIp:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4.

In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0.In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4.

In another aspect, provided herein is a method of inhibiting15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each X is independently selected from N and CR⁷;    -   Y is selected from O, S, SO₂, and C(R⁸)₂;    -   R¹ is selected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;        wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally        substituted with 1 to 3 substituents independently selected from        halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,        —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo or thio;    -   R⁴ and R⁵ are independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; wherein        each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is        independently optionally substituted with 1 to 3 substituents        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl; or    -   R⁴ and R⁵ are taken together, along with the nitrogen atom to        which they are attached, to form a 3-to 10-membered        heterocycloalkyl optionally substituted with 1 to 3 substituents        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   each R⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or two R⁶'s attached to the same carbon        atom are taken together to form oxo, thio, or C₃₋₁₀cycloalkyl,        and any remaining R⁶'s are independently selected from halo,        —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,        —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,        C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl,        and 5- to 10-membered heteroaryl;    -   each R⁷ is independently selected from H, halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl;    -   each R⁸ is independently selected from H, halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or    -   two R⁸'s can be taken together to form a C₃₋₁₀cycloalkyl        optionally substituted with 1 to 3 substituents independently        selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,        —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,        —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to        10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl;    -   R⁹ and R¹⁰ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R¹¹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹² is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   m is 1 or 2; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, each X is independently selected from N and CR⁷. Insome embodiments, at least one X is N and the rest are CR⁷. In someembodiments, at least two X are N and the rest are CR⁷. In someembodiments, each X is N. In some embodiments, each X is CR⁷.

In some embodiments, Y is selected from O, S, SO₂, and C(R⁸)₂. In someembodiments, Y is O. In some embodiments, Y is S. In some embodiments, Yis SO₂. In some embodiments, Y is C(R⁸)₂.

In some embodiments, R¹ is selected from C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, R¹ is selected from C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein the aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁹R¹⁰,—OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,—NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, R¹ is selected fromC₆₋₁₀aryl and 5- to 10-membered heteroaryl; wherein the aryl orheteroaryl is optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆ heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5-to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionallysubstituted with 1 to 3 substituents independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, R¹ is selected from C₆₋₁₀aryl and5- to 10-membered heteroaryl; wherein the aryl or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, R² is H and R³ is —CF₃. In some embodiments, R² andR³ are taken together to form oxo. In some embodiments, R² and R³ aretaken together to form thio.

In some embodiments, R⁴ and R⁵ are independently selected fromC₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; whereineach alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5-to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ areindependently selected from C₃₋₁₀cycloalkyl; wherein each cycloalkyl isindependently optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5-to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ areindependently selected from C₃₋₁₀cycloalkyl; wherein each cycloalkyl isindependently optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R⁴ and R⁵ are independently selectedfrom C₃₋₁₀cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are independentlyselected from C₃₋₁₀cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, R⁴ and R⁵ are taken together, along with thenitrogen atom to which they are attached, to form a 3- to 10-memberedheterocycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, R⁴ and R⁵ are taken together, along with the nitrogen atomto which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, R⁴ and R⁵ are taken together, along with the nitrogen atomto which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are taken together, alongwith the nitrogen atom to which they are attached, to form a 3-to10-membered heterocycloalkyl optionally substituted with 1 to 3substituents independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, each R⁶ is independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl. In some embodiments, each R⁶ is independently selected fromhalo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹⁰, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, eachR⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,—NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and —NR¹³SO₂NR⁹R¹⁰. In some embodiments,each R⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, two R⁶'s attached to the same carbon atom are takentogether to form oxo, thio, or C₃₋₁₀cycloalkyl, and any remaining R⁶'sare independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,—NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-memberedheterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, two R⁶'s attached to the same carbon atom are takentogether to form oxo, thio, or C₃₋₁₀cycloalkyl, and any remaining R⁶'sare independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,—NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, two R⁶'sattached to the same carbon atom are taken together to form oxo, thio,or C₃₋₁₀cycloalkyl, and any remaining R⁶'s are independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, two R⁶'s attached to the samecarbon atom are taken together to form oxo, thio, or C₃₋₁₀cycloalkyl,and any remaining R⁶'s are independently selected from halo, —NR⁹R¹⁰,—OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, each R⁷ is independently selected from H, halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl. In some embodiments, each R⁷ is independently selected fromH, halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, each R⁷ is independently selected from H, halo, —NR⁹R¹⁰,—OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,—NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and —NR¹³SO₂NR⁹R¹⁰. In someembodiments, each R⁷ is independently selected from H, halo, —NR⁹R¹⁰,—OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, each R⁸ is independently selected from H, halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl. In some embodiments, each R⁸ is independently selected fromH, halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, each R⁸ is independently selected from H, halo, —NR⁹R¹⁰,—OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,—NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and —NR¹³SO₂NR⁹R¹⁰. In someembodiments, each R⁸ is independently selected from H, halo, —NR⁹R¹⁰,—OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, two R⁸'s can be taken together to form aC₃₋₁₀cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5-to 10-membered heteroaryl. In some embodiments, two R⁸'s can be takentogether to form a C₃₋₁₀cycloalkyl optionally substituted with 1 to 3substituents independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,—NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, two R⁸'s can betaken together to form a C₃₋₁₀cycloalkyl optionally substituted with 1to 3 substituents independently selected from halo, —NR⁹R¹⁰, —OR¹¹,—C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,—NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and —NR¹³SO₂NR⁹R¹⁰. In someembodiments, two R⁸'s can be taken together to form a C₃₋₁₀cycloalkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, R⁹ and R¹⁰ are independently selected at eachoccurrence from H, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, R⁹ and R¹⁰ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R⁹ and R¹⁰ are independentlyselected at each occurrence from H and C₁₋₆alkyl.

In some embodiments, each R¹¹ is independently selected from H,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R¹¹ isindependently selected from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R¹¹ is independently selectedfrom H and C₁₋₆alkyl.

In some embodiments, each R¹² is independently selected from C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R¹² is independentlyselected from C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, each R¹² is independently selected from C₁₋₆alkyl.

In some embodiments, each R¹³ is independently selected from H,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, eachR¹³ is independently selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl. Insome embodiments, each R¹³ is independently selected from H andC₁₋₆alkyl.

In some embodiments, m is 1 or 2. In some embodiments, m is 1. In someembodiments, m is 2.

In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0.In some embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3. In some embodiments, n is 4.

In some embodiments, the compound is a compound of Formula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R¹⁴ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; and    -   p is 0, 1, 2, or 3.

In some embodiments, each R¹⁴ is independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R¹⁴ isindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆ alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R¹⁴ is independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R¹⁴ is independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰. In someembodiments, each R¹⁴ is independently halo. In some embodiments, eachR¹⁴ is independently fluoro.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In some embodiments, the compound is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IIId:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each R¹⁴ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆        alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; and    -   p is 0, 1, 2, or 3.

In some embodiments, each R¹⁴ is independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R¹⁴ isindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆ alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R¹⁴ is independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R¹⁴ is independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰. In someembodiments, each R¹⁴ is independently halo. In some embodiments, eachR¹⁴ is independently fluoro.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

Compounds

In one aspect, provided herein is a compound of Formula IIk:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   T, U, and Y are independently selected from N and CR⁶, provided        that when U is N, at least one of T and Y is N;    -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein the aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁷R⁸,        —OR⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸,        —NR¹¹C(O)R⁹, —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹SO₂NR⁷R⁸,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and        5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   each R⁴ is independently selected from H and halo;    -   R⁵ is selected from halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹,        —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,        —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹SO₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R⁶ is selected from H, halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹,        —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,        —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹SO₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R⁷ and R⁸ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl;    -   each R⁹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹¹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₆cycloalkyl; and    -   p is 0, 1, or 2.

In some embodiments, T, U, and Y are independently selected from N andCR⁶, provided that when U is N, at least one of T and Y is N. In someembodiments, one of T, U, and Y is N and the rest are CR⁶. In someembodiments, two of T, U, and Y are N and the rest are CR⁶. In someembodiments, one of T, U, and Y is CR⁶ and the rest are N. In someembodiments, two of T, U, and Y are CR⁶ and the rest are N. In someembodiments, T, U, and Y are N. In some embodiments, T, U, and Y areCR⁶.

In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein the aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁷R⁸, —OR⁹,—C(O)R⁹, —C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,—NR¹¹C(O)NR⁷R⁸, —NR¹¹O₂R⁹, —NR¹¹SO₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆ heteroalkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, and 5- to 10-membered heteroaryl. In someembodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein the aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁷R⁸, —OR⁹,—C(O)R⁹, —C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,—NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹SO₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆heteroalkyl,and C₁₋₆haloalkyl. In some embodiments, R¹ is selected from C₆₋₁₀aryland 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰,—SO₂NR⁷R⁸, —NR¹¹C(O)R⁹, —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, and —NR¹¹SO₂NR⁷R⁸.In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein the aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁷R⁸, —OR⁹,—C(O)R⁹, —C(O)OR⁹, and —C(O)NR⁷R⁸.

In some embodiments, R² is H and R³ is —CF₃. In some embodiments, R² andR³ are taken together to form oxo.

In some embodiments, each R⁴ is independently selected from H and halo.In some embodiments, each R⁴ is independently selected from H andfluoro. In some embodiments, each R⁴ is H. In some embodiments, each R⁴is fluoro. In some embodiments, one R⁴ is H and one R⁴ is fluoro.

In some embodiments, R⁵ is selected from halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹,—C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,—NR¹¹C(O)NR⁷R⁸, —NR¹¹O₂R⁹, —NR¹¹SO₂NR⁷R⁸, C₁₋₆ alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3- to 10-membered heterocycloalkyl,C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁵ isselected from halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰,—SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹, —NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹,—NR¹¹O₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆ haloalkyl. In someembodiments, R⁵ is selected from halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹,—C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹, —NR¹¹C(O)NR⁷R⁸,—NR¹¹O₂R⁹, and —NR¹¹SO₂NR⁷R⁸. In some embodiments, R⁵ is selected fromhalo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹, and —C(O)NR⁷R⁸.

In some embodiments, R⁶ is selected from H, halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹,—C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,—NR¹¹C(O)NR⁷R⁸, —NR¹¹SO₂R⁹, —NR¹¹O₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3- to 10-membered heterocycloalkyl,C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁶ isselected from H, halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁷R⁸,—SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹, —NR¹¹C(O)NR⁷R⁸, —NR¹¹O₂R⁹,—NR¹¹O₂NR⁷R⁸, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆ haloalkyl. In someembodiments. R⁶ is selected from H, halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹,—C(O)OR⁹, —C(O)NR⁷R⁸, —SOR¹⁰, —SO₂R¹⁰, —SO₂NR⁷R⁸, —NR¹¹C(O)R⁹,—NR¹¹C(O)NR⁷R⁸, —NR¹¹O₂R⁹, and —NR¹¹O₂NR⁷R⁸. In some embodiments, R⁶ isselected from H, halo, —NR⁷R⁸, —OR⁹, —C(O)R⁹, —C(O)OR⁹, and —C(O)NR⁷R⁸.

In some embodiments, R⁷ and R⁸ are independently selected at eachoccurrence from H, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, R⁷ and R⁸ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R⁷ and R⁸ are independently selectedat each occurrence from H and C₁₋₆alkyl.

In some embodiments, each R⁹ is independently selected from H,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R⁹ isindependently selected from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R⁹ is independently selectedfrom H and C₁₋₆alkyl.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R¹⁰ is independentlyselected from C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, each R¹⁰ is independently selected from C₁₋₆alkyl.

In some embodiments, each R¹¹ is independently selected from H,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₁₋₆cycloalkyl. In some embodiments, eachR¹¹ is independently selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl. Insome embodiments, each R¹¹ is independently selected from H andC₁₋₆alkyl.

In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2.

In another aspect, provided herein is a compound of Formula IIm:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein said aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁶R⁷,        —OR⁹, —C(O)R⁹, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and        5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; or    -   two R⁴'s are taken together with the carbon atoms to which they        are attached and any intervening atoms to form a        C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently        selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷,        —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,        —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,        C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl;    -   R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,        —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,        —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁸ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   p is 0, 1, 2, or 3.

In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein said aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁶R⁷, —OR,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆ heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and 5- to 10-membered heteroaryl. Insome embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein said aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,and C₁₋₆haloalkyl. In some embodiments, R¹ is selected from C₆₋₁₀aryland 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷.In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein said aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.

In some embodiments, R² is H and R³ is —CF₃. In some embodiments, R² andR³ are taken together to form oxo.

In some embodiments, each R⁴ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R⁴ is independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,—NR¹⁰SO₂NR⁶R⁷, C₁₋₆ alkyl, C₁₋₆heteroalkyl, and C₁₋₆ haloalkyl. In someembodiments, each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, eachR⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,and —C(O)NR⁶R⁷. In some embodiments, each R⁴ is independently selectedfrom halo. In some embodiments, each R⁴ is fluoro.

In some embodiments, two R⁴'s are taken together with the carbon atomsto which they are attached and any intervening atoms to form aC₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently selected fromhalo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸. —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, two R⁴'s aretaken together with the carbon atoms to which they are attached and anyintervening atoms to form a C₃₋₁₀cycloalkyl, and any remaining R⁴'s areindependently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,—NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, two R⁴'s are taken together with thecarbon atoms to which they are attached and any intervening atoms toform a C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and—NR¹⁰SO₂NR⁶R⁷. In some embodiments, two R⁴'s are taken together with thecarbon atoms to which they are attached and any intervening atoms toform a C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.

In some embodiments, R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl,C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁵ isselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,—NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆ haloalkyl. In someembodiments, R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,—NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, R⁵ is selected fromhalo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.

In some embodiments, R⁶ and R⁷ are independently selected at eachoccurrence from H, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, R⁶ and R⁷ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl. In some embodiments, R⁶ and R⁷ are independently selectedat each occurrence from H and C₁₋₆alkyl.

In some embodiments, each R⁸ is independently selected from H,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ isindependently selected from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R⁸ is independently selectedfrom H and C₁₋₆alkyl.

In some embodiments, each R⁹ is independently selected from C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R⁹ is independentlyselected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl. In someembodiments, each R⁹ is independently selected from C₁₋₆alkyl.

In some embodiments, each R¹⁰ is independently selected from H,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, eachR¹⁰ is independently selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl. Insome embodiments, each R¹⁰ is independently selected from H andC₁₋₆alkyl.

In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. Insome embodiments, n is 2. In some embodiments, n is 3. In someembodiments, n is 4.

In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, m is 0. In some embodiments, m is 1. In some embodiments, mis 2. In some embodiments, m is 3. In some embodiments, m is 4. In someembodiments, m is 5. In some embodiments, m is 6. In some embodiments, mis 7. In some embodiments, m is 8. In some embodiments, m is 9. In someembodiments, m is 10.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In another aspect, provided herein is a compound of Formula IIq:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein said aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁶R⁷,        —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and        5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,        —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,        —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; or    -   two R⁴'s are taken together with the carbon atoms to which they        are attached and any intervening atoms to form a        C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently        selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷,        —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,        —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,        C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₁₀aryl, and 5- to 10-membered        heteroaryl;    -   R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,        —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,        —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆        heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered        heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   R⁶ and R⁷ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R⁸ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl;    -   n is 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   p is 0, 1, 2, or 3.

In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein said aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆ heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and 5- to 10-membered heteroaryl. Insome embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein said aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR³, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,and C₁₋₆haloalkyl. In some embodiments, R¹ is selected from C₆₋₁₀aryland 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁹, and —NR¹⁰SO₂NR⁶R⁷.In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein said aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.

In some embodiments, R² is H and R³ is —CF₃. In some embodiments, R² andR³ are taken together to form oxo.

In some embodiments, each R⁴ is independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷—, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R⁴ is independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,—NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆ haloalkyl. In someembodiments, each R⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, eachR⁴ is independently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,and —C(O)NR⁶R⁷. In some embodiments, each R⁴ is independently selectedfrom halo. In some embodiments, each R⁴ is fluoro.

In some embodiments, two R⁴'s are taken together with the carbon atomsto which they are attached and any intervening atoms to form aC₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently selected fromhalo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, two R⁴'s aretaken together with the carbon atoms to which they are attached and anyintervening atoms to form a C₃₋₁₀cycloalkyl, and any remaining R⁴'s areindependently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,—NR¹⁰SO₂R⁹, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆ heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, two R⁴'s are taken together with thecarbon atoms to which they are attached and any intervening atoms toform a C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸. —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, and—NR¹⁰SO₂NR⁶R⁷. In some embodiments, two R⁴'s are taken together with thecarbon atoms to which they are attached and any intervening atoms toform a C₃₋₁₀cycloalkyl, and any remaining R⁴'s are independentlyselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.

In some embodiments, R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl,C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁵ isselected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹,—SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸,—NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆ haloalkyl. In someembodiments, R⁵ is selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,—NR¹⁰SO₂R⁸, and —NR¹⁰SO₂NR⁶R⁷. In some embodiments, R⁵ is selected fromhalo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.

In some embodiments, R⁶ and R⁷ are independently selected at eachoccurrence from H, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, R⁶ and R⁷ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₁₋₆haloalkyl. In some embodiments, R⁶ and R⁷ are independently selectedat each occurrence from H and C₁₋₆alkyl.

In some embodiments, each R⁸ is independently selected from H,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ isindependently selected from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R⁸ is independently selectedfrom H and C₁₋₆alkyl.

In some embodiments, each R⁹ is independently selected from C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R⁹ is independentlyselected from C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl. In someembodiments, each R⁹ is independently selected from C₁₋₆alkyl.

In some embodiments, each R¹⁰ is independently selected from H,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, eachR¹⁰ is independently selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl. Insome embodiments, each R¹⁰ is independently selected from H andC₁₋₆alkyl.

In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. Insome embodiments, n is 2. In some embodiments, n is 3. In someembodiments, n is 4.

In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, m is 0. In some embodiments, m is 1. In some embodiments, mis 2. In some embodiments, m is 3. In some embodiments, m is 4. In someembodiments, m is 5. In some embodiments, m is 6. In some embodiments, mis 7. In some embodiments, m is 8. In some embodiments, m is 9. In someembodiments, m is 10.

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3.

In another aspect, provided herein is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each X is independently selected from N and CR⁷;    -   Y is selected from O, S, SO₂, and C(R⁸)₂;    -   R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl;        wherein the aryl or heteroaryl is optionally substituted with 1        to 3 substituents independently selected from halo, —NR⁹R¹⁰,        —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,        —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,        C₃₋₆cycloalkyl, and 5- to 10-membered heteroaryl;    -   R² is H and R³ is —CF₃; or    -   R² and R³ are taken together to form oxo;    -   R⁴ and R⁵ are independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₆ cycloalkyl; wherein        each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is        independently optionally substituted with 1 to 3 substituents        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 3-        to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to        10-membered heteroaryl; or    -   R⁴ and R⁵ are taken together, along with the nitrogen atom to        which they are attached, to form a 3- to 10-membered        heterocycloalkyl optionally substituted with 1 to 3 substituents        independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃cycloalkyl,        C₆₋₁₀aryl, and 5- to 10-membered heteroaryl;    -   each R⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹,        —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,        —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 3- to        10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered        heteroaryl; or    -   two R⁶'s attached to the same carbon atom are taken together to        form oxo, and any remaining R⁶'s are independently selected from        halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,        —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃₋₆cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl,        and 5- to 10-membered heteroaryl;    -   each R⁷ and R⁸ is independently selected from halo, —NR⁹R¹⁰,        —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,        —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,        —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,        C₃-cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl,        and 5- to 10-membered heteroaryl;    -   R⁹ and R¹⁰ are independently selected at each occurrence from H,        C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, and C₃₋₁₀cycloalkyl;    -   each R¹¹ is independently selected from H, C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, and        5- to 10-membered heteroaryl;    -   each R¹² is independently selected from C₁₋₆alkyl,        C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃cycloalkyl, C₆₋₁₀ aryl, and 5-        to 10-membered heteroaryl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; and    -   n is 0, 1, 2, 3, or 4.

In some embodiments, each X is independently selected from N and CR⁷. Insome embodiments, at least one X is N and the rest are CR⁷. In someembodiments, at least two X are N and the rest are CR⁷. In someembodiments, each X is N. In some embodiments, each X is CR⁷.

In some embodiments, Y is selected from O, S, SO₂, and C(R⁸)₂. In someembodiments, Y is O. In some embodiments, Y is S. In some embodiments, Yis SO₂. In some embodiments, Y is C(R⁸)₂.

In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to 10-memberedheteroaryl; wherein the aryl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from halo, —NR⁹R¹⁰,—OR), —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,—NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,C₁₋₆ heteroalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, and 5- to 10-memberedheteroaryl. In some embodiments, R¹ is selected from C₆₋₁₀aryl and 5- to10-membered heteroaryl; wherein the aryl or heteroaryl is optionallysubstituted with 1 to 3 substituents independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, R¹is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl; wherein thearyl or heteroaryl is optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, and —NR¹³SO₂NR⁹R¹⁰. In some embodiments, R¹ is selectedfrom C₆₋₁₀aryl and 5- to 10-membered heteroaryl; wherein the aryl orheteroaryl is optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,and —C(O)NR⁹R¹⁰.

In some embodiments, R² is H and R³ is —CF₃. In some embodiments, R² andR³ are taken together to form oxo.

In some embodiments, R⁴ and R⁵ are independently selected fromC₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; whereineach alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆ haloalkyl,C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5-to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ areindependently selected from C₃₋₁₀cycloalkyl; wherein each cycloalkyl isindependently optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5-to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ areindependently selected from C₃₋₁₀cycloalkyl; wherein each cycloalkyl isindependently optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R⁴ and R⁵ are independently selectedfrom C₃₋₁₀cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are independentlyselected from C₃₋₁₀cycloalkyl; wherein each cycloalkyl is independentlyoptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, R⁴ and R⁵ are taken together, along with thenitrogen atom to which they are attached, to form a 3- to 10-memberedheterocycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹,—C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰,—NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl. In someembodiments, R⁴ and R⁵ are taken together, along with the nitrogen atomto which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, R⁴ and R⁵ are taken together, along with the nitrogen atomto which they are attached, to form a 3- to 10-membered heterocycloalkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are taken together, alongwith the nitrogen atom to which they are attached, to form a 3-to10-membered heterocycloalkyl optionally substituted with 1 to 3substituents independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, each R⁶ is independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl. In some embodiments, each R⁶ is independently selected fromhalo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹². —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, eachR⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,—NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and —NR¹³SO₂NR⁹R¹⁰. In some embodiments,each R⁶ is independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, two R⁶'s attached to the same carbon atom are takentogether to form oxo, and any remaining R⁶'s are independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹²,—SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5-to 10-membered heteroaryl. In some embodiments, two R⁶'s attached to thesame carbon atom are taken together to form oxo, and any remaining R⁶'sare independently selected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹,—NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl,C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In some embodiments, two R⁶'sattached to the same carbon atom are taken together to form oxo, and anyremaining R⁶'s are independently selected from halo, —NR⁹R¹⁰, —OR¹¹,—C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰,—NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and —NR¹³SO₂NR⁹R¹⁰. In someembodiments, two R⁶'s attached to the same carbon atom are takentogether to form oxo, and any remaining R⁶'s are independently selectedfrom halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and —C(O)NR⁹R¹⁰.

In some embodiments, each R⁷ and R⁸ is independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, —NR¹³SO₂NR⁹R¹⁰,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3- to10-membered heterocycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl. In some embodiments, each R⁷ and R⁸ is independentlyselected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰,—SOR¹², —SO₂R¹², —SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹,—NR¹³SO₂NR⁹R¹⁰, C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, each R⁷ and R⁸ is independently selected from halo,—NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)NR⁹R¹⁰, —SOR¹², —SO₂R¹²,—SO₂NR⁹R¹⁰, —NR¹³C(O)R¹¹, —NR¹³C(O)NR⁹R¹⁰, —NR¹³SO₂R¹¹, and—NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R⁷ and R⁸ is independentlyselected from halo, —NR⁹R¹⁰, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, and—C(O)NR⁹R¹⁰.

In some embodiments, R⁹ and R¹⁰ are independently selected at eachoccurrence from H, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl. In some embodiments, R⁹ and R¹⁰ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, R⁹ and R¹⁰ are independentlyselected at each occurrence from H and C₁₋₆alkyl.

In some embodiments, each R¹¹ is independently selected from H,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl,and 5- to 10-membered heteroaryl. In some embodiments, each R¹¹ isindependently selected from H, C₁₋₆alkyl, C₁₋₆heteroalkyl, andC₁₋₆haloalkyl. In some embodiments, each R¹¹ is independently selectedfrom H and C₁₋₆alkyl.

In some embodiments, each R¹² is independently selected from C₁₋₆alkyl,C₁₋₆heteroalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl. In some embodiments, each R¹² is independentlyselected from C₁₋₆alkyl, C₁₋₆heteroalkyl, and C₁₋₆haloalkyl. In someembodiments, each R¹² is independently selected from C₁₋₆alkyl.

In some embodiments, each R¹³ is independently selected from H,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl. In some embodiments, eachR¹³ is independently selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl. Insome embodiments, each R¹³ is independently selected from H andC₁₋₆alkyl.

In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0.In some embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3. In some embodiments, n is 4.

In another aspect, provided herein is a composition comprising acompound selected from the group consisting of:

In another aspect, provided herein is a composition comprising acompound selected from the group consisting of:

In another aspect, provided herein is a composition comprising acompound selected from the group consisting of:

In some cases, the solubility and hPGDH IC50 of the inhibitors arecharacterized as shown in Tables 1 and 2.

TABLE 1 Characteristics of PGDH Inhibitors with a 6-5 ring core. hPGDH:Solubility at Structure IC50 (uM) pH 7.4 (μM)

0.0574 140

0.0195 140

0.0201 160

0.0006

0.0025

1.2593

2.8696

0.0449

0.0471

0.1579

4.5407

0.0056

0.0647

0.2736

0.5757

0.0057

0.0052

0.0018 34

0.0122

0.0466

0.0027 120

0.439 16

0.1164

0.0032

0.0249 33

0.0015 21

0.0106

0.1968 45

0.0128 150

0.0493 <5.0

0.0031 68

0.0437 160

0.0064 150

0.0058 6.9

0.0005 <5.0

TABLE 2 Characteristics of PGDH Inhibitors with a phenyl core. hPGDH:IC50 Solubility at pH Structure (uM) 7.4 (μM)

0.135

0.2772

0.0085

2.2838 160

0.0186 38

0.0271 29

0.5933 88

0.0031 6.3

Provided in Table 3 are analytical data for some of the inhibitorsdescribed herein.

TABLE 3 Analytical data for select inhibitors Mass Spec. Calculated/Mass Spec. ¹H NMR (DMSO-d₆*, 400 MHz) Target No Structure Yield/PurityFound (m/z) (*unless otherwise indicated) MF- PGDH-015

 10.5%/98.06% 365.13 for C21H20ClN3O/ 366.0 (M + 1) δ 8.69 (s, 1H),7.86-7.89 (m, 2H), 7.65-7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.48 (dd, J =1.5, 8.4 Hz, 1H), 3.69 (br s, 2H), 3.37 (br d, J = 8.8 Hz, 1H), 3.26 (brs, 1H), 2.61- 2.68 (m, 2H), 1.65-1.79 (m, 3H), 1.48-1.60 (m, 2H),1.29-1.41 (m, 1H). MF- PGDH-016

 8.6%/98.08% 353.13 for C20H20ClN3O/ 354.0 (M + 1) δ 8.69 (s, 1H), 7.87(t, J = 1.8 Hz, 1H), 7.65-7.75 (m, 4H), 7.57-7.61 (m, 1H), 7.32-7.36 (m,1H), 3.59 (br t, J = 5.3 Hz, 2H), 3.37 (br s, 2H), 1.75 (br s, 2H),1.52-1.62 (m, 6H). MF- PGDH-017

 9.8%/98.72% 337.10 for C19H16ClN3O/ 338.0 (M + 1) δ 8.69-8.69 (m, 1H),7.86-7.87 (m, 2H), 7.65-7.73 (m, 3H), 7.58- 7.61 (m, 1H), 7.44 (dd, J =1.5, 8.4 Hz, 1H), 3.97-4.02 (m, 1H), 3.72 (br d, J = 8.3 Hz, 1H),3.36-3.42 (m, 2H), 1.56 (br d, J = 1.3 Hz, 2H), 0.62-0.68 (m, 1H), 0.12(q, J = 4.1 Hz, 1H). MF- PGDH-018

 13.7%/97.46% 365.13 for C21H20ClN3O/ 366.0 (M + 1) δ 8.68 (s, 1H), 7.86(t, J = 2.0 Hz, 1H), 7.70-7.73 (m, 2H), 7.64-7.69 (m, 2H), 7.57-7.61 (m,1H), 7.33 (dd, J = 1.4, 8.4 Hz, 1H), 4.29-4.43 (m, 1H), 3.32-3.42 (m,1H), 3.17- 3.28 (m, 1H), 2.76-3.00 (m, 1H), 2.04-2.33 (m, 2H), 1.49-1.67(m, 5H), 1.31-1.45 (m, 1H). MF- PGDH-019

 16.6%/92.94% 351.11 for C20H18ClN3O/ 352.0 (M + 1) δ 8.72 (s, 1H), 8.03(s, 1H), 7.88 (t, J = 1.9 Hz, 1H), 7.60-7.74 (m, 5H), 4.35 (br s, 2H),4.07 (br s, 2H), 2.19 (t, J = 7.6 Hz, 4H), 1.76- 1.83 (m, 2H). MF-PGDH-023

 4.8%/98.86% 339.11 for C19H18ClN3O/ 340.00 (M + 1) δ 8.70 (s, 1H), 7.88(s, 1H), 7.75 (m, 1H), 7.63-7.73 (m, 3H), 7.57- 7.61 (m. 1H), 7.35-7.39(m, 1H), 3.35-3.70 (br s, 4H), 1.45-1.70 (m, 6H). MF- PGDH-025

 4.6%/99.70% 341.09 for C18H16ClN3O2/ 342.0 (M + 1) δ 8.70 (s, 1H), 7.86(t, J = 1.9 Hz, 1H), 7.83 (d, J = 1.0 Hz, 1H), 7.65-7.73 (m, 3H),7.58-7.61 (m, 1H), 7.41 (dd, J = 1.5, 8.4 Hz, 1H), 3.62 (br s, 5H), 3.55(br d, J = 9.9 Hz, 3H). MF- PGDH-026

 8.8%/98.37% 375.09 for C₂₃H₂₈ClFN₄O₃/ 376.0 (M + 1) δ 8.70 (s, 1H),7.86-7.89 (m, 2H), 7.65-7.74 (m, 3H), 7.58-7.61 (m, 1H), 7.43-7.46 (m,1H), 3.52-3.73 (m, 4H), 2.07 (br d, J = 5.1 Hz, 4H). MF- PGDH-046

 23.3%/99.32% 325.10 for C18H16ClN3O/ 326.2 (M + 1) δ 8.69 (s, 1H), 7.93(d, J = 0.9 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.65- 7.73 (m, 3H),7.58-7.61 (m, 1H), 7.51-7.54 (m, 1H), 3.44-3.53 (m, 4H), 1.78-1.93 (m,4H). MF- PGDH-047

23.46%/99.75% 361.08 for C18H41ClF2N3O/ 362.2 (M + 1) δ 8.72 (s, 1H),7.99 (d, J = 0.98 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.65- 7.74 (m, 3H),7.54-7.62 (m, 2H), 3.90-4.00 (m, 2H), 3.76 (t, J = 7.4 Hz, 2H),2.39-2.47 (m, 2H). MF- PGDH-048

 23.2%/99.56% 343.09 for C18H15ClFN3O/ 344.2 (M + 1) δ 8.71 (s, 1H),7.96 (br d, J = 7.58 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.64-7.74 (m,3H), 7.51-7.62 (m, 2H), 5.22-5.48 (m, 1H), 3.51-3.97 (m, 4H), 2.03-2.26(m, 2H). MF- PGDH-049

  57%/99.51% 359.06 for C18H15Cl2N3O/ 360.1 (M + 1) δ 8.71 (s, 1H), 7.95(br d, J = 13.6 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.65-7.74 (m, 3H),7.58-7.62 (m, 1H), 7.51-7.57 (m, 1H), 4.72-4.87 (m, 1H), 3.91-4.09 (m,1H), 3.74- 3.81 (m, 1H), 3.52-3.67 (m, 2H), 2.37-2.45 (m, 1H), 2.08-2.20(m, 1H). MF- PGDH-050

  64%/99.53% 341.09 for C18H16ClN3O2/ 342.2 (M + 1) δ 8.70 (s, 1H),7.86-7.92 (m, 2H), 7.66-7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.51-7.54 (m,1H), 4.91-5.03 (m, 1H), 4.22-4.37 (m, 1H), 3.41- 3.67 (m, 4H), 1.78-1.99(m, 2H). MF- PGDH-052

11.34%/99.89% 355.11 for C19H18ClN3O2/ 356.2 (M + 1) δ 8.69 (s, 1H),7.87 (t, J = 1.9 Hz, 1H), 7.77 (d, J = 1.0 Hz, 1H), 7.64- 7.73 (m, 3H),7.58-7.61 (m, 1H), 7.37 (dd, J = 1.5, 8.31 Hz, 1H), 4.77 (d, J = 4.0 Hz,1H), 3.87-4.1 (m, 1H), 3.75 (dt, J = 4.2, 8.16 Hz, 1H), 3.21 (br s, 2H),1.70-1.83 (m, 2H), 1.32-1.44 (m, 2H). MF- PGDH-063

11.09%/99.48% 311.08 for C17H14ClN3O/ 312.0 (M + 1) δ 8.70 (s, 1H), 8.50(br d, J = 4.0 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H), 7.85-7.89 (m, 2H),7.64-7.74 (m, 3H), 7.57-7.62 (m, 1H), 2.85-2.93 (m, 1H), 0.58-0.73 (m,4H). MF- PGDH-065

20.22%/99.07% 347.08 for C20H14ClN3O/ 348.1 (M + 1) δ 10.31 (s, 1H),8.76 (s, 1H), 8.51 (d, J = 1.3 Hz, 1H), 7.98-8.02 (m, 1H), 7.89-7.91 (m,1H), 7.84 (d, J = 7.6 Hz, 2H), 7.73-7.78 (m, 2H), 7.67-7.71 (m, 1H),7.60-7.63 (m, 1H), 7.34-7.39 (m, 2H), 7.08-7.12 (m, 1H). MF- PGDH-103

 7.58%/99.74% 299.08 for C16H14ClN3O/ 300.2 (M + 1) δ 8.69 (s, 1H), 7.87(t, J = 1.9 Hz, 1H), 7.82 (d, J = 0.9 Hz, 1H), 7.65- 7.73 (m, 3H),7.58-7.61 (m, 1H), 7.40 (dd, J = 1.5, 8.4 Hz, 1H), 3.00 (br s, 6H). MF-PGDH-104

23.91%/98.08% 311.08 for C17H14ClN3O/ 312.2 (M + 1) δ 8.71 (s, 1H), 8.00(d, J = 0.8 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.58- 7.73 (m, 5H), 4.36(br t, J = 6.7 Hz, 2H), 4.08 (br t, J = 6.8 Hz, 2H), 2.24-2.31 (m, 2H).MF- PGDH-105

 11.5%/99.69% 339.11 for C19H18ClN3O/ 340.0 (M + 1) δ 8.71 (s, 1H), 8.02(s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.63-7.73 (m, 4H), 7.58-7.61 (m, 1H),4.05 (s, 2H), 3.76 (s, 2H), 1.26 (s, 6H). MF- PGDH-106

  57%/97.93% 329.07 for C17H13ClFN3O/ 330.1 (M + 1) δ 8.73 (s, 1H), 8.05(s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.59-7.73 (m, 5H), 5.36-5.56 (m, 1H),4.33-4.74 (m, 3H), 4.03-4.23 (m, 1H). MF- PGDH-107

 9.8%/99.89% 345.04 for C17H13Cl2N3O/ 345.9 (M + 1) δ 8.73 (s, 1H), 8.03(s, 1H), 7.87- 7.88 (m, 1H), 7.64-7.74 (m, 4H), 7.59-7.62 (m, 1H), 4.88(dd, J = 4.0, 6.5 Hz, 2H), 4.61-4.69 (m, 1H), 4.43-4.52 (m, 1H),4.06-4.18 (m, 1H). MF- PGDH-051

  57%/98.33% 340.11 for C18H17ClN4O/ 341.2 (M + 1) δ 8.70 (s, 1H),7.85-7.96 (m, 2H), 7.65-7.73 (m, 3H), 7.49-7.61 (m, 2H), 3.58-3.70 (m,3H), 3.40-3.55 (m, 3H), 3.15-3.27 (m, 1H), 1.97- 2.07 (m, 1H), 1.66-1.75(m, 1H). MF- PGDH-064

 6.84%/99.68% 325.10 for C18H16ClN3O/ 326.2 (M + 1) δ 8.68 (s, 1H), 7.94(s, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.71-7.74 (m, 1H), 7.64-7.69 (m, 2H),7.57-7.61 (m, 1H), 7.49-7.52 (m, 1H), 3.00 (s, 4H), 0.40-0.56 (m, 4H).MF- PGDH-090

 3.85%/91.38% 339.08 for C18H14ClN3O2/ 340.2 (M + 1) CDCl₃ δ 8.19-8.19(m, 1H), 8.04 (s, 1H), 7.58-7.61 (m, 2H), 7.55 (dd, J = 2.7, 4.9 Hz,2H), 7.49-7.52 (m, 1H), 7.42-7.45 (m, 1H), 4.05- 4.16 (br s, 2H),3.76-3.79 (m, 1H), 3.62-3.65 (m, 1H), 2.67 (br t, J = 7.8 Hz, 2H). MF-PGDH-102

69.51%/99.99% 271.05 for C14H10ClN3O/ 272.1 (M + 1) δ 8.70 (s, 1H), 8.36(s, 1H), 8.05 (br s, 1H), 7.91-7.93 (m, 1H), 7.87 (s, 1H), 7.68-7.73 (m,3H), 7.66-7.67 (m, 1H), 7.59 (br d, J = 7.7 Hz, 1H). MF- PGDH-027

 7.55%/99.90% 411.13 for C22H22ClN3O3/ 412.0 (M + 1) δ 7.88-7.89 (m,1H), 7.79 (t, J = 1.77 Hz, 1H), 7.60-7.69 (m, 2H), 7.54-7.58 (m, 1H),7.42 (dd, J = 1.47, 8.56 Hz, 1H), 7.24 (dd, J = 0.61, 8.44 Hz, 1H), 4.25(q, J = 7.09 Hz, 2H), 3.48-3.68 (m, 2H), 3.33-3.47 (m, 2H), 1.45-1.67(m, 6H), 1.18 (t, J = 7.09 Hz, 4H). MF- PGDH-030

 13.7%/94.95% 425.15 for 23H24ClN3O3/ 426.0 (M + 1) δ 7.72-7.74 (m, 1H),7.66-7.69 (m, 3H), 7.53-7.56 (m, 1H), 7.21- 7.29 (m, 2H), 4.05 (s, 2H),3.93- 3.99 (m, 2H), 3.37-3.68 (m, 4H), 1.60-1.64 (m, 2H), 1.45-1.58 (m,4H), 1.05 (t, J = 7.09 Hz, 3H). MF- PGDH-091

 2.9%/98.92% 353.13 for C20H20ClN3O/ 354.2 (M + 1) δ 7.78-7.79 (m, 1H),7.65-7.70 (m, 2H), 7.56-7.62 (m, 2H), 7.17- 7.23 (m, 2H), 3.41-3.65 (m,4H), 2.46 (s, 3H), 1.59-1.64 (m, 2H), 1.46-1.57 (m, 4H). MF- PGDH-033

 7.1%/97.95% 425.15 for C24H26ClN3O3/ 426.0 (M + 1) δ 7.77-7.79 (m, 1H),7.67-7.73 (m, 2H), 7.63-7.66 (m, 1H), 7.56- 7.61 (m, 1H), 7.16-7.24 (m,2H), 3.57 (s, 3H), 3.38-3.51 (m, 2H), 2.89-3.01 (m, 4H), 1.46-1.66 (m,6H). MF- PGDH-034

 3.6%/95.15% 411.13 for C22H22ClN3O3/ 426.0 (M + 1) δ 7.77-7.78 (m, 1H),7.68-7.71 (m, 2H), 7.63-7.64 (m, 1H), 7.56- 7.60 (m, 1H), 7.16-7.25 (m,2H), 6.97-7.15 (m, 2H), 3.39-3.56 (m, 3H), 2.92-2.96 (m, 2H), 2.80-2.85(m, 2H), 1.62 (br d, J = 3.55 Hz, 2H), 1.51 (br s, 4H). MF- PGDH-035

 17.3%/97.93% 410.15 for C22H23ClN4O2/ 411.3 (M + 1) δ 7.79-7.80 (m,1H), 7.67-7.70 (m, 2H), 7.57-7.63 (m, 2H), 7.40 (br s, 1H), 7.15-7.23(m, 2H), 6.80 (br s, 1H), 3.34-3.61 (m, 4H), 2.89-2.94 (m, 2H),2.66-2.70 (m, 2H), 1.47-1.65 (m, 6H). MF- PGDH-008

 13.5%/96.97% 335.16 for C20H21N3O2/ 336.1 (M + 1) δ 8.55 (s, 1H), 7.74(s, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.32 (dd, J= 8.3, 1.5 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 3.52-3.40(m, 4H), 1.62-1.51 (m, 6 H). MF- PGDH-009

 18.2%/99.52% 353.15 for C20H20FN3O2/ 354.0 (M + 1) δ 8.56 (s, 1H), 7.80(d, J = 0.98 Hz, 1H), 7.54-7.63 (m, 3H), 7.36 (dd, J = 1.47, 8.4 Hz,1H), 7.16-7.20 (m, 2H), 4.83-5.01 (m, 1H), 3.85 (s, 3H), 3.43-3.70 (m,4H), 1.84- 2.00 (m, 2H), 1.74 (br d, J = 2.9 Hz, 2H). MF- PGDH-021

 14.6%/99.43% 375.19 for C23H25N3O22/ 376.0 (M + 1) δ 7.50-7.54 (m, 3H),7.14-7.22 (m, 3H), 7.07-7.10 (m, 1H), 3.87 (s, 3H), 3.35-3.55 (m, 3H),1.78- 1.86 (m, 1H), 1.45-1.65 (m, 6H), 1.21-1.28 (m, 1H), 1.10-1.14 (m,2H), 0.98-1.03 (m, 2H). MF- PGDH-022

  51%/99.72% 336.16 for C19H20N4O2/ 337.1 (M + 1) δ 8.92 (s, 1H), 8.36(d, J = 2.93 Hz, 1H), 8.17 (d, J = 8.44 Hz, 1H), 7.91 (d, J = 8.93 Hz,1H), 7.75- 7.70 (m, 2H), 7.37 (dd, J = 1.53, 8.38 Hz, 1H), 3.92 (s, 3H),3.56- 3.37 (m, 4H), 1.63-1.53 (m, 6H). MF- PGDH-024

 45.3%/99.10% 369.12 for C20H20ClN3O2/ 370.2 (M + 1) δ 8.68 (s, 1H),7.76 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.49(d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.3, 1.5 Hz, 1H), 7.32-7.29 (dd, J =8.4, 2.3 Hz, 1H), 3.97 (s, 3H), 3.50-3.46 (m, 4H), 1.63-1.53 (m, 6 H)MF- PGDH-062

 23.6%/97.72% 349.14 for C20H19N3O3/ 350.0 (M + 1) δ 8.54 (s, 1H), 7.73(s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.35-7.31 (m, 2H), 7.18-7.06 (m, 2H),6.17 (s, 2H), 3.53-3.41 (m, 4H), 1.63-1.52 (m, 6 H). MF- PGDH-141

 14.5%/99.11% 325.13 for C19H19FN4O2/ 326.1 (M + 1) δ 9.12 (s, 1H), 9.03(d, J = 5.8 Hz, 1H), 8.94 (d, J = 5.77 Hz, 1H), 8.54-8.52 (m, 2H), 8.24(d, J = 1.92 Hz, 1H), 6.94 (d, J = 3.84 Hz, 1H), 5.02-4.97 (m, 1H), 3.93(s, 3H), 3.60 (m, 4H), 1.99-1.75 (m, 6H). MF- PGDH-061

 34.8%/98.88% 355.11 for C19H18ClN3O2/ 356.2 (M + 1) δ 10.83 (br s, 1H),8.62 (s, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.64 (dd, J = 0.5, 8.3 Hz, 1H),7.59 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.4, 1.5 Hz, 1H), 7.23 (d, J =2.6 Hz, 1H), 7.14 (dd, J = 8.4, 2.4 Hz, 1H), 3.54- 3.42 (m, 4H), 3.32(s, 3H) 1.63- 1.53 (m, 6 H). MF- PGDH-014

 21.4%/99.15% 339.11 for C19H18ClN3O/ 340.0 (M + 1) δ 8.39 (s, 1H),8.18-8.07 (m, 3H), 7.94-7.87 (m, 1H), 7.62- 7.55 (m, 1H), 7.46-7.38 (m,1H), 6.82 (s, 1H), 3.67-3.38 (m, 4H), 1.68-1.43 (m, 6H) MF- PGDH-067

 21.0%/99.65% 306.15 for C18H18N4O/ 307.3 (M + 1) δ 8.85 (d, J = 8.3 Hz,1H), 8.55 (dd, J = 1.0, 4.8 Hz, 1H), 8.47 (d, J = 3.8 Hz, 1H), 8.43 (d,J = 2.0 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.06 (ddd, J = 2.0, 7.4, 8.3Hz, 1H), 7.36 (ddd, J = 0.8, 4.9, 7.3 Hz, 1H), 6.84 (d, J = 3.9 Hz, 1H),3.73-3.37 (m, 4H), 1.71-1.42 (m, 6H) MF- PGDH-068

 37.5%/99.00% 306.15 for C18H18N4O/ 307.2 (M + 1) δ 9.14 (d, J = 2.4 Hz,1H), 8.58 (dd, J = 1.6, 4.8 Hz, 1H), 8.38 (dd, J = 1.6, 2.8 Hz, 1H),8.36 (t, J = 2.0 Hz, 1H), 8.15-8.13 (m, 2H), 7.63-7.60 (m, 1H), 6.85 (d,J = 3.6 Hz, 1H), 3.59-3.42 (m, 4H), 1.68-1.43 (m, 6H) MF- PGDH-069

 2.3%/97.98% 307.14 for C17H17N5O/ 308.2 (M + 1) δ 9.12 (d, J = 1.0 Hz,1H), 9.03 (dd, J = 1.3, 5.7 Hz, 1H), 8.94 (d, J = 5.7 Hz, 1H), 8.53 (d,J = 4.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H),6.93 (d, J = 4.0 Hz, 1H), 3.72-3.35 (m, 4H), 1.71-1.40 (m, 6H) MF-PGDH-070

 15.2%/99.91% 307.14 for C17H17N5O/ 308.2 (M + 1) δ 9.47 (s, 2H), 9.18(s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 3.7 Hz, 1H), 8.18 (d, J= 2.1 Hz, 1H), 6.91 (d, J = 3.8 Hz, 1H), 3.79-3.37 (m, 4H), 1.74-1.40(m, 6H) MF- PGDH-071

 19.3%/99.50% 307.14 for C17H17N5O/ 308.2 (M + 1) δ 10.10 (d, J = 1.3Hz, 1H), 8.69- 8.58 (m, 2H), 8.48 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 3.8Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 3.8 Hz, 1H), 3.75-3.39(m, 4H), 1.75-1.43 (m, 6H) MF- PGDH-073

 31.5%/95.38% 323.17 for C18H21N5O/ 324.1 (M + 1) δ 8.37 (br s, 1H),8.10 (br s, 2H), 7.93-7.59 (m, 2H), 6.73 (br s, 1H), 4.11 (q, J = 7.1Hz, 2H), 3.74-3.35 (m, 4H), 1.71-1.48 (m, 6H), 1.42 (t, J = 7.2 Hz, 3H)MF- PGDH-074

 30.4%/99.72% 312.10 for C16H16N4OS/ 313.0 (M + 1) δ 9.22 (d, J = 1.8Hz, 1H), 8.44 (d, J = 1.1 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.29 (d, J= 3.7 Hz, 1H), 8.16 (d, J = 1.5 Hz, 1H), 6.81 (d, J = 3.7 Hz, 1H), 3.76-3.36 (m, 4H), 1.78-1.36 (m, 6H) MF- PGDH-075

 26.8%/99.41% 295.14 for C16H17N5O/ 296.0 (M + 1) δ 13.34-12.77 (m, 1H),8.42 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 8.11 (d, J = 2.0Hz, 1H), 7.98 (d, J = 3.4 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 3.69- 3.41(m, 4H), 1.73-1.46 (m, 6H) MF- PGDH-076

 34.5%/98.55% 309.16 for C17H19N5O/ 310.1 (M + 1) δ 8.43 (s, 1H), 8.35(d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 0.6 Hz, 1H),7.96 (d, J = 3.5 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1H), 3.93 (s, 3H),3.69-3.37 (m, 4H), 1.77-1.39 (m, 6H) MF-DH- 123

 30.9%/99.52% 325.13 for C17H16FN5O/ 326.1 (M + 1) δ 10.11 (d, J = 1.3Hz, 1H), 8.68- 8.61 (m, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 3.9Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 3.8 Hz, 1H), 5.08-4.84(m, 1H), 3.85-3.54 (m, 4H), 2.07- 1.73 (m, 4H) MF-DH- 128

 48.2%/99.68% 415.20 for C24H25N5O2/ 416.1 (M + 1) δ 8.36 (br s, 1H),8.17-8.04 (m, 2H), 7.83 (br d, J = 16.0 Hz, 2H), 7.35 (d, J = 8.6 Hz,2H), 6.96 (d, J = 8.7 Hz, 2H), 6.74 (br s, 1H), 5.25 (s, 2H), 3.75 (s,3H), 3.66- 3.37 (m, 4H), 1.79-1.43 (m, 6H) MF-DH- 129

 45.8%/99.17% 415.20 for C24H25N5O2/ 416.1 (M + 1) δ 8.52 (d, J = 0.6Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 1.4, 3.2 Hz, 2H), 7.98(d, J = 3.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H),6.74 (d, J = 3.7 Hz, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.66-3.35 (m, 4H),1.72- 1.43 (m, 6H) MF-DH- 131

 48.2%/99.11% 325.13 for C17H16FN5O/ 326.1 (M + 1) δ 9.12 (s, 1H), 9.03(d, J = 5.8 Hz, 1H), 8.94 (d, J = 5.8 Hz, 1H), 8.59-8.49 (m, 2H), 8.24(d, J = 1.9 Hz, 1H), 6.94 (d, J = 3.8 Hz, 1H), 5.05-4.81 (m, 1H), 3.83-3.36 (m, 4H), 2.04-1.64 (m, 4H) MF-132

 11.2%/98.86% 359.09 for C17H15ClFN5O/ 360.0 (M + 1) δ 9.14 (s, 1H),8.96 (s, 2H), 8.69 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 1.8Hz, 1H), 5.13- 4.80 (m, 1H), 3.88-3.43 (m, 4H), 2.05-1.65 (m, 4H) MF-133

 2.02%/92.41% 340.13 for C18H17FN4O2/ 341.0 (M + 1) CDCl₃ δ 8.42 (s,1H), 8.21 (br s, 1H), 8.11 (br d, J = 1.2 Hz, 2H), 7.46 (d, J = 3.5 Hz,1H), 6.96 (br d, J = 9.4 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 5.72-5.37(m, 1H), 5.06-4.83 (m, 1H), 4.15-3.41 (m, 4H), 2.20-1.72 (m, 4H) MF-134

 19.7%/99.09% 324.14 for C18H17FN4O/ 325.0 (M + 1) δ 9.15 (br s, 1H),8.59 (br d, J = 3.7 Hz, 1H), 8.46-8.34 (m, 2H), 8.20 (d, J = 2.0 Hz,1H), 8.15 (d, J = 3.7 Hz, 1H), 7.62 (dd, J = 4.7, 8.3 Hz, 1H), 6.86 (d,J = 3.8 Hz, 1H), 5.11-4.80 (m, 1H), 3.79- 3.39 (m, 4H), 2.09-1.64 (m,4H) MF-135

 5.4%/98.86% 358.10 for C18H16ClFN4O/ 359.0 (M + 1) δ 9.12 (d, J = 2.4Hz, 1H), 8.61 (dd, J = 1.3, 4.8 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.43(s, 1H), 8.38- 8.29 (m, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.63 (dd, J =4.8, 8.3 Hz, 1H), 5.15-4.76 (m, 1H), 3.88- 3.41 (m, 4H), 2.09-1.62 (m,4H) MF-139

 12.2%/99.18% 327.15 for C17H18FN5O/ 328.2 (M + 1) δ 8.43 (s, 1H), 8.39(d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 0.7 Hz, 1H),7.97 (d, J = 3.7 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 5.08-4.76 (m, 1H),3.93 (s, 3H), 3.73-3.43 (m, 4H), 2.03- 1.67 (m, 4H) MF-140

 2.6%/99.84% 361.11 for C17H17ClFN5O/ 362.0 (M + 1) δ 8.48 (d, J = 1.8Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.01 (s,1H), 5.07-4.76 (m, 1H), 3.93 (s, 3H), 3.79-3.38 (m, 4H), 2.10-1.66 (m,4H) MF-145

 36.5%/98.03% 359.09 for C17H15ClFN5O/ 360.0 (M + 1) δ 9.43 (s, 2H),9.21 (s, 1H), 8.58- 8.44 (m, 2H), 8.19 (d, J = 2.0 Hz, 1H), 5.15-4.74(m, 1H), 3.85- 3.39 (m, 4H), 2.10-1.59 (m, 4H) MF-157

 7.4%/99.53% 354.15 for C19H19FN4O2/ 355.1 (M + 1) δ 8.60 (d, J = 2.6Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.27-8.13 (m, 2H), 8.00 (d, J = 3.7Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 3.7 Hz, 1H), 5.10-4.77(m, 1H), 3.93 (s, 3H), 3.78-3.44 (m, 4H), 2.05-1.68 (m, 4H) MF- PGDH-020

 13.7%/99.94% 340.11 for C18H17ClN4O/ 341.0 (M + 1) δ 9.11 (s, 1H), 8.51(d, 1H), 8.30 (d, 1H), 8.20-8.22 (m, 1H), 8.01- 8.03 (m, 1H), 7.70-7.72(m, 1H), 7.57-7.59 (m, 1H), 3.54-3.67 (m, 2H), 3.34-3.42 (m, 2H),1.48-1.68 (m, 6H). MF- PGDH-077

 14.8%/99.66% 336.16 for C19H20N4O2/ 337.2 (M + 1) δ 8.89 (s, 1H), 8.43(d, J = 1.83 Hz, 1H), 8.20 (d, J = 1.96 Hz, 1H), 7.78-7.82 (m, 2H),7.15-7.19 (m, 2H), 3.84 (s, 3H), 3.54-3.68 (m, 2H), 3.34-3.45 (m, 2H),1.49-1.67 (m, 6H). MF- PGDH-078

  15%/99.73% 354.15 for C19H19FN4O2/ 355.2 (M + 1) δ 8.90 (s, 1H),8.47-8.48 (d, J = 1.83 Hz, 1H), 8.25-8.26 (d, J = 1.96 Hz, 1H),7.79-7.81 (m, 2H), 7.13-7.15 (m, 2H), 4.82-5.01 (m, 1H), 3.84-3.85 (s,3H), 3.52- 3.80 (m, 4H), 1.83-2.01 (m, 2H), 1.71-1.82 (m, 2H). MF-PGDH-079

 5.5%/98.59% 372.14 for C19H18F2N4O2/ 373.2 (M + 1) δ 8.90 (s, 1H),8.50-8.51 (d, J = 1.83 Hz, 1H), 8.30-8.31 (d, J = 1.96 Hz, 1H),7.79-7.81 (m, 2H), 7.16-7.18 (m, 2H), 3.84-3.85 (s, 3H), 3.55-3.70 (m,4H), 2.03- 2.12 (m, 4H). MF-DH- 138

 13.1%/99.72% 326.12 for C17H15FN4O2/ 327.0 (M + 1) δ 8.92 (s, 1H), 8.70(d, J = 1.92 Hz, 1H), 8.42 (d, J = 1.92 Hz, 1H), 7.78-7.81 (m, 2H), 7.17(d, J = 8.97 Hz, 2H), 5.38-5.55 (m, 1H), 4.41-4.71 (m, 3H), 4.09-4.19(m, 1H), 3.85 (s, 3H). MF-DH- 115

 3.96%/98.04% 369.16 for C19H20FN5O2/ 370.1 (M + 1) δ 7.78 (d, J = 1.83Hz, 1H), 7.41 (d, J = 1.83 Hz, 1H), 7.31-7.34 (m, 2H), 7.06 (d, J = 8.93Hz, 2H), 6.64 (s, 2H), 4.75-4.94 (m, 1H), 3.77 (s, 3H), 3.51 (br d, J =0.86 Hz, 4H), 1.79-1.88 (m, 2H), 1.67 (br d, J = 2.20 Hz, 2H). MF-DH-116

 2.12%/99.12% 411.17 for C21H22FN5O3/ 410.1 (M − 1) δ 10.49-10.64 (m,1H), 8.21-8.23 (m, 1H), 8.00 (br s, 1H), 7.32- 7.34 (m, 2H), 7.02-7.05(m, 2H), 4.77-4.94 (m, 1H), 3.77 (s, 3H), 3.48-3.62 (m, 4H), 1.82-1.94(m, 7H). MF- PGDH-036

 2.05%/99.77% 373.07 for C19H20BrNO2/ 375.9 (M + 3) δ 7.60 (dd, J =1.53, 7.89 Hz, 1H), 7.53 (d, J = 8.07 Hz, 2H), 7.36- 7.42 (m, 2H),7.32-7.35 (m, 1H), 7.21 (dd, J = 1.22, 8.31 Hz, 1H), 6.91 (dt, J = 1.28,7.61 Hz, 1H), 5.25 (s, 2H), 3.57 (br s, 2H), 3.27 (br s, 2H), 1.39-1.65(m, 6H) MF- PGDH-037

2.1%/99%  329.12 for C19H20ClNO2/ 330.1 (M + 1) δ 7.52 (d, J = 8.1 Hz,2H), 7.47- 7.38 (m, 3H), 7.33-7.22 (m, 2H), 6.97 (dt, J = 1.5, 7.6 Hz,1H), 5.25 (s, 2H), 3.57 (br s, 2H), 3.22-3.30 (m, 2H), 1.65-1.41 (m,6H). MF- PGDH-038

 2.1%/99.95% 359.13 for C20H22ClNO3/ 360.0 (M + 1) δ 7.40-7.53 (m, 2H),7.29 (dd, J = 1.53, 7.40 Hz, 1H), 7.18-7.26 (m, 1H), 7.03 (d, J = 1.10Hz, 1H), 6.95-7.00 (m, 2H), 5.17 (s, 2H), 3.86 (s, 3H), 3.48-3.66 (m,2H), 3.19-3.30 (m, 2H), 1.39-1.66 (m, 6H). MF- PGDH-039

 1.4%/98.03% 345.10 for C19H20ClNOS/ 346.0 (M + 1) δ 7.69-7.78 (m, 3H),7.46-7.50 (m, 1H), 7.22-7.28 (m, 4H), 4.89 (s, 2H), 3.48-3.58 (m, 2H),3.08- 3.17 (m, 2H), 1.39-1.62 (m, 6H). MF- PGDH-040

 9.6%/99.38% 377.09 for C19H20ClNO3/ 378.0 (M + 1) δ 7.69-7.78 (m, 3H),7.45-7.51 (m, 1H), 7.25 (d, J = 1.34 Hz, 4H), 4.89 (s, 2H), 3.54 (brs,2H), 3.12 (brs, 2H), 1.56-1.63 (m, 2H), 1.34-1.55 (m, 4H). MF- PGDH-045

  68%/99.84% 361.09 for C19H20ClNO2S/ 362.0 (M + 1) δ 7.51-7.60 (m, 2H),7.40-7.45 (m, 1H), 7.29-7.33 (m, 1H), 7.19- 7.22 (m, 2H), 7.02-7.05 (m,2H), 4.39-4.45 (m, 1H), 4.17-4.21 (m, 1H), 3.47-3.61 (m, 2H), 3.12-3.20(m, 2H), 1.57-1.65 (m, 2H), 1.38- 1.56 (m, 4H). MF- PGDH-038

30.37%/99.95% 359.13 for C20H22ClNO3/ 360.0 (M + 1) δ 7.40-7.53 (m, 2H),7.29 (dd, J = 1.53, 7.40 Hz, 1H), 7.18-7.26 (m, 1H), 7.03 (d, J = 1.10Hz, 1H), 6.95-7.00 (m, 2H), 5.17 (s, 2H), 3.86 (s, 3H), 3.48-3.66 (m,2H), 3.19-3.30 (m, 2H), 1.39-1.66 (m, 6H). MF-DH- 118

 14.6%/99.53% 377.12 for C20H21ClFNO3/ 378.0 (M + 1) δ 7.43-7.51 (m,2H), 7.31 (dt, J = 1.59, 7.83 Hz, 1H), 7.18-7.26 (m, 1H), 7.08 (d, J =1.10 Hz, 1H), 6.95-7.03 (m, 2H), 5.17 (s, 2H), 4.82-5.01 (m, 1H), 3.86(s, 4H), 3.34-3.76 (m, 4H), 1.62-2.02 (m, 4H). MF-DH- 121

 61.4%/99.67% 348.01 for C18H18ClFN2O2/ 349.0 (M + 1) δ 8.67-8.71 (m,1H), 8.01 (dd, J = 2.02, 8.01 Hz, 1H), 7.64 (d, J = 7.95 Hz, 1H), 7.46(dd, J = 1.47, 7.82 Hz, 1H), 7.26-7.36 (m, 2H), 7.00 (dt, J = 1.59, 7.52Hz, 1H), 5.31 (s, 2H), 4.83-5.02 (m, 1H), 3.70 (br t, J = 5.50 Hz, 2H),3.43- 3.55 (m, 1H), 3.33-3.40 (m, 1H), 1.64-2.03 (m, 4H). MF- PGDH-095

 12.4%/99.23% 372.18 for C24H24N2O2/ 373.1 (M + 1) δ 8.65-8.68 (m, 1H),7.88-7.92 (m, 1H), 7.77-7.82 (m, 1H), 7.71- 7.74 (m, 1H), 7.47 (d, J =8.19 Hz, 2H), 7.30-7.42 (m, 4H), 7.21-7.25 (m, 1H), 7.06-7.11 (m, 1H),5.24 (s, 2H), 3.52-3.62 (m, 2H), 3.20- 3.30 (m, 2H), 1.58-1.64 (m, 2H),1.41-1.56 (m, 4H). MF- PGDH-096

 2.05%/99.19% 378.14 for C22H23N3O2/ 379.0 (M + 1) δ 11.63-12.41 (m,1H), 8.04 (br d, J = 7.09 Hz, 1H), 7.71 (s, 1H), 7.56 (d, J = 8.07 Hz,2H), 7.36-7.48 (m, 3H), 7.11-7.20 (m, 2H), 6.99 (t, J = 7.21 Hz, 1H),5.28 (s, 2H), 3.57 (br d, J = 2.32 Hz, 2H), 3.43-3.52 (m, 2H), 1.43-1.65(m, 6H). MF- PGDH-097

 30.9%/99.72% 326.12 for C22H22N2O2S/ 327.0 (M + 1) δ 9.06 (s, 1H), 8.38(s, 1H), 7.80 (br d, J = 7.34 Hz, 1H), 7.53-7.57 (m, 2H), 7.34-7.42 (m,3H), 7.26- 7.29 (m, 1H), 7.07 (t, J = 7.34 Hz, 1H), 5.32 (s, 2H),3.53-3.62 (m, 2H), 3.20-3.34 (m, 2H), 1.43-1.65 (m, 6H). MF- PGDH-041

 3.53%/98.91% 338.16 for C20H22N2O3/ 339.1 (M + 1) δ 10.28 (s, 1H), 7.79(d, J = 8.56 Hz, 2H), 7.61 (dd, J = 1.71, 7.58 Hz, 1H), 7.51 (ddd, J =1.83, 7.40, 8.38 Hz, 1H), 7.35 (d, J = 8.56 Hz, 2H), 7.18 (d, J = 8.19Hz, 1H), 7.07 (dt, J = 0.86, 7.46 Hz, 1H), 3.89 (s, 3H), 3.48-3.63 (m,2H), 3.37-3.47 (m, 2H), 1.61 (br d, J = 4.16 Hz, 2H), 1.51 (br s, 4H).MF- PGDH-042

16.71%/99.67% 352.18 for C21H42N2O3/ 353.1 (M + 1) δ 7.04-7.27 (m, 6H),6.67-6.89 (m, 2H), 3.42-3.59 (m, 5H), 3.31 (br s, 3H), 2.99-3.12 (m,2H), 1.31-1.57 (m, 6H). MF- PGDH-087

 4.77%/92.51% 374.14 for C20H20F2N2O3/ 375.0 (M + 1) δ 10.30 (s, 1H),7.81 (d, J = 8.56 Hz, 2H), 7.61 (dd, J = 1.71, 7.58 Hz, 1H), 7.48-7.54(m, 1H), 7.44 (d, J = 8.56 Hz, 2H), 7.19 (d, J = 8.19 Hz, 1H), 7.07 (s,1H), 3.89 (s, 3H), 3.47-3.68 (m, 4H), 1.98- 2.10 (m, 4H). MF- PGDH-088

 66.1%/98.39% 342.11 for C19H19ClN2O2/ 343.2 (M + 1) δ 10.67 (s, 1H),7.77 (d, J = 8.56 Hz, 2H), 7.44-7.61 (m, 4H), 7.37 (d, J = 8.56 Hz, 2H),3.36-3.68 (m, 4H), 1.57-1.66 (m, 2H), 1.42-1.56 (m, 4H). MF- PGDH-089

 2.49%/93.52% 338.16 for C20H22N2O3/ 339.2 (M + 1) δ 10.36 (s, 1H),7.80-7.86 (m, 2H), 7.52-7.56 (m, 1H), 7.43-7.49 (m, 2H), 7.35-7.39 (m,2H), 7.15- 7.19 (m, 1H), 3.84-3.85 (s, 3H), 3.34-3.64 (m, 4H), 1.46-1.65(m, 6H). MF- PGDH-043

  90%/94.19% 338.16 for C20H22N2O3/ 339.1 (M + 1) δ 9.53 (s, 1H),7.98-8.01 (m, 2H), 7.71-7.76 (m, 1H), 7.48-7.51 (m, 2H), 7.19-7.21 (m,1H), 7.09-7.12 (m, 1H), 6.92-7.01 (m, 1H), 3.82 (s, 3H), 3.60 (br s,2H), 3.21 (br s, 2H), 1.41-1.72 (m, 6H). MF- PGDH-044

23.69%/99.96% 352.18 for C21H24N2O3/ 353.1 (M + 1) δ 7.08-7.31 (m, 6H),6.93 (br d, J = 8.19 Hz, 1H), 6.84 (br t, J = 7.46 Hz, 1H), 3.68 (s,3H), 3.50 (br s, 2H), 3.22 (s, 3H), 3.00-3.13 (m, 2H), 1.53-1.61 (m,2H), 1.24-1.52 (m, 4H). MF- PGDH-004

 2.7%/99.50% 338.12 for C20H19ClN2O/ 339.0 (M + 1) δ 7.79 (d, J = 3.4Hz, 1H), 7.73- 7.68 (m, 2H), 7.64-7.58 (m, 3H), 7.50-7.47 (m, 1H),7.26-7.22 (m, 1H), 6.79 (dd, J = 0.6, 3.3 Hz, 1H), 3.48 (br s, 4H), 1.62(br d, J = 4.4 Hz, 2H), 1.52 (br s, 4H). MF- PGDH-005

 3.5%/99.35% 372.08 for C20H18Cl2N2O/ 372.9 (M + 1) δ 8.08 (s, 1H),7.76-7.75 (m, 1H), 7.66-7.61 (m, 3H), 7.59 (d, J = 1.5 Hz, 1H),7.50-7.53 (m, 1H), 7.31- 7.35 (m, 1H), 3.34-3.65 (m, 4H), 1.62 (br d, J= 3.9 Hz, 2H), 1.44- 1.58 (m, 4H). MF- PGDH-053

   2%/98.66% 338.12 for C20H19ClN2O/ 339.2 (M + 1) ¹H NMR (400 MHz,DMSO-d₆): δ 11.65 (br s, 1H), 7.93-7.88 (m, 2H), 7.27-7.68 (m, 2H),7.51-7.42 (m, 2H), 7.29-7.26 (m, 1H), 7.13- 7.09 (m, 1H), 3.62-3.40 (m,4H), 1.68-1.43 (m, 6H). MF- PGDH-054

 81.4%/99.81% 352.13 for C21H21ClN2O/ 353.2 (M + 1) δ 7.93-7.88 (m, 2H),7.70-7.65 (m, 2H), 7.57 (d, J = 0.7 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H),7.29 (ddd, J = 0.9, 2.1, 8.0 Hz, 1H), 7.16 (dd, J = 1.3, 8.19 Hz, 1H),3.87 (s, 3H), 3.66-3.40 (m, 4H), 1.67-1.48 (m, 6H). MF- PGDH-057

 7.0%/95.07% 354.15 for C21H23ClN2O/ 355.2 (M + 1) δ 7.42-7.37 (m, 1H),7.30 (t, J = 2.0 Hz, 1H), 7.23 (ddd, J = 0.9, 2.1, 8.1 Hz, 1H), 7.17(ddd, J = 0.9, 2.0, 8.1 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.97 (dd, J =2.0, 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 3.63-3.58 (m, 2H), 3.44 (brs, 4H), 2.81-2.77 (m, 2H), 1.99- 1.92 (m, 2H), 1.64-1.56 (m, 2H), 1.48(br d, J = 3.7 Hz, 4H). MF- PGDH-058

 8.2%/98.34% 368.13 for C21H21ClN2O2/ 369.0 (M + 1) δ 7.60-7.52 (m, 2H),7.46 (t, J = 1.7 Hz, 1H), 7.33-7.26 (m, 2H), 7.12-7.08 (m, 1H), 6.25 (d,J = 8.3 Hz, 1H), 3.69-3.35 (m, 4H), 3.07 (br t, J = 7.3 Hz, 2H),2.76-2.71 (m, 2H), 1.64-1.56 (m, 2H), 1.55- 1.42 (m, 4H). MF- PGDH-006

 4.41%/99.75% 339.11 for C19H18ClN3O/ 340.0 (M + 1) δ 8.49 (s, 1H),7.96-7.89 (m, 2H), 7.94-7.88 (m, 1H), 7.85-7.81 (m, 1H), 7.64-7.61 (m,1H), 7.55-7.51 (m, 2H), 3.69-3.31 (m, 4H), 1.71- 1.42 (m, 6H). MF-PGDH-007

 15.7%/98.0% 339.11 for C19H18ClN3O/ 340.0 (M + 1) δ 8.64-8.61 (m, 1H),7.92 (s, 1H), 7.79 (s, 1H), 7.68-7.62 (m, 2H), 7.59-7.54 (m, 1H),7.52-7.49 (m, 1H), 6.99-6.95 (m, 1H), 3.69-3.35 (m, 4H), 1.69-1.45 (m,6H). MF- PGDH-011

45.29%/97.16% 340.11 for C18H17ClN4O/ 341.0 (M + 1) δ 8.21 (s, 1H),8.03-8.00 (m, 2H), 7.92-7.89 (m, 1H), 7.76-7.65 (m, 3H), 3.73-3.52 (m,2H), 1.70-1.21 (m, 8H). MF- PGDH-012

 9.9%/98.76% 340.11 for C18H17ClN4O/ 341.0 (M + 1) δ 9.33 (d, J = 2.1Hz, 1H), 8.94 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.28 (t, J = 1.8 Hz,1H), 8.14-8.10 (m, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.34- 7.30 (m, 1H),3.66-3.43 (m, 4H), 1.67-1.54 (m, 6H). MF-DH- 150

 35.7%/99.98% 339.15 for C18H18FN5O/ 340.1 (M + 1) δ 10.10 (d, J = 1.2Hz, 1H), 8.58- 8.64 (m, 2H), 8.36 (d, J = 3.9 Hz, 1H), 8.30 (s, 1H),7.02 (d, J = 3.9 Hz, 1H), 4.82-5.02 (m, 1H), 3.64- 3.90 (m, 2H),3.34-3.41 (m, 1H), 3.11-3.26 (m, 1H), 2.50 (s, 3H), 1.60-2.08 (m, 4H).MF-DH- 151

 6.1%/99.45% 373.11 for C18H17ClFN5O/ 374.0 (M + 1) δ 9.98 (s, 1H), 8.63(s, 2H), 8.46 (s, 1H), 8.36 (s, 1H), 4.82-5.04 (m, 1H), 3.84 (br s, 1H),3.65- 3.76 (m, 1H), 3.14-3.23 (m, 1H), 2.70 (s, 3H), 1.70-2.03 (m, 4H).MF-DH- 161

 17.0%/99.13% 408.16 for C20H20F4N4O/ 409.1 (M + 1) δ 8.39-8.43 (m, 1H),8.30-8.33 (m, 1H), 8.16 (d, J = 2.45 Hz, 1H), 7.35-7.41 (m, 2H), 7.29(s, 1H), 5.52-5.60 (m, 1H), 4.82-5.01 (m, 1H), 3.36-3.71 (m, 4H),2.74-2.83 (m, 1H), 2.61-2.69 (m, 1H), 1.67- 2.04 (m, 6H). MF-DH- 164

 18.6%/92.70% 340.17 for C19H21FN4O/ 341.1 (M + 1) δ 8.89 (s, 1H), 8.77(s, 2H), 7.17 (s, 1H), 7.03 (br d, J = 8.3 Hz, 1H), 6.72-6.75 (m, 1H),4.80-4.96 (m, 1H), 3.66 (t, J = 5.8 Hz, 2H), 3.45- 3.60 (m, 4H), 2.81(t, J = 6.41 Hz, 2H), 1.86-2.00 (m, 4H), 1.65-1.72 (m, 2H). MF-DH- 162

 7.5%/99.77% 354.19 for C20H23FN4O/ 355.1 (M + 1) δ 8.55 (s, 1H),8.24-8.32 (m, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H),7.28-7.35 (m, 1H), 7.17 (dd, J = 1.7, 8.3 Hz, 1H), 4.82-5.01 (m, 1H),3.83 (t, J = 6.2 Hz, 2H), 3.38-3.67 (m, 4H), 2.86- 2.97 (m, 1H),2.04-2.13 (m, 1H), 1.81-2.01 (m, 2H), 1.58-1.79 (m, 3H), 1.29 (d, J =7.0 Hz, 3H). MF-DH- 160

 16.7%/98.63% 368.20 for C21H25FN4O/ 369.1 (M + 1) δ 8.53-8.58 (s, 1H),8.27-8.30 (s, 1H), 8.08-8.1.1 (m, 1H), 7.42 (s, 1H), 7.32-7.39 (m, 1H),7.11-7.17 (m, 1H), 4.82-5.00 (m, 1H), 3.82- 3.91 (m, 2H), 3.41-3.71 (m,4H), 1.81-1.98 (m, 2H), 1.68-1.81 (m, 4H), 1.29 (s, 6H) MF-DH- 167

 16.5%/99.68% 373.11 for C18H17ClFN5O/ 374.0 (M + 1) δ 9.82 (s, 1H),8.56-8.63 (m, 1H), 8.50-8.56 (m, 2H), 8.18 (d, J = 1.83 Hz, 1H),4.85-5.04 (m, 1H), 3.40-3.88 (m, 4H), 2.58 (s, 3H), 1.69-2.05 (m, 4H).MF-DH- 168

 9.5%/98.46% 373.11 for C18H17ClFN5O/ 374.0 (M + 1) δ 8.76 (d, J = 2.4Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.15-8.23(m, 2H), 4.83-5.02 (m, 1H), 3.38-3.79 (m, 4H), 2.43 (s, 3H), 1.85-2.02(m, 2H), 1.69- 1.83 (m, 2H). MF-DH- 159

 5.48%/99.36% 342.15 for C18H19FN4O2/ 343.1 (M + 1) ¹H NMR (400 MHz,DMSO-d₆): δ 8.64 (s, 1H), 8.31 (br s, 1H), 8.14 (d, J = 2.4 Hz, 1H),7.55 (d, J = 8.3 Hz, 1H), 6.86-7.00 (m, 2H), 4.81-5.01 (m, 1H),4.23-4.38 (m, 2H), 4.02 (br d, J = 4.2 Hz, 2H), 3.39-3.67 (m, 4H),1.82-1.99 (m, 2H), 1.65-1.79 (m, 2H). MF-DH- 207

 30.3%/99.84% 366.16 for C21H22N2O4/ 367.2 (M + 1) ¹H NMR (400 MHz,DMSO-d₆): δ 6.89-7.00 (m, 2H), 6.69-6.82 (m, 3H), 6.53 (d, J = 8.2 Hz,1H), 6.05 (s, 2H), 4.24-4.33 (m, 2H), 3.57-3.69 (m, 2H), 3.42 (br s,4H), 1.59 (br d, J = 4.4 Hz, 2H), 1.40-1.53 (m, 4H). MF-DH- 209

 2.2%/93.69% 352.18 for C21H24N2O3/ 353.2 (M + 1) ¹H NMR (400 MHz,DMSO-d₆): δ 7.24 (br d, J = 8.8 Hz, 2H), 7.00 (br d, J = 8.8 Hz, 2H),6.78 (d, J = 1.5 Hz, 1H), 6.71 (br d, J = 8.4 Hz, 1H), 6.49 (s, 1H),4.30 (br s, 2H), 3.77 (s, 3H), 3.60-3.72 (m, 2H), 3.43 (br s, 4H), 1.59(br d, J = 3.7 Hz, 2H), 1.47 (br s, 4H). MF-DH- 203

20.36%/99.43% 303.17 for C17H22FN3O/ 304.1 (M + 1) δ 8.33 (s, 1H), 7.87(d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.28 (brd, J = 8.4 Hz, 1H), 4.82-5.01(m, 1H), 3.37- 3.68 (m, 4H), 1.82-1.99 (m, 2H), 1.67-1.77 (m, 11H).MF-DH- 165

 7.2%/97.23% 326.15 for C18H19FN4O/ 327.1 (M + 1) δ 8.26-8.37 (m, 3H),8.11 (d, J = 2.6 Hz, 1H), 7.31 (s, 1H), 7.23- 7.30 (m, 1H), 4.82-5.00(m, 1H), 4.18 (t, J = 8.7 Hz, 2H), 3.41-3.66 (m, 4H), 3.22-3.28 (m, 2H),1.81- 1.99 (m, 2H), 1.64-1.78 (m, 2H). MF-DH- 311

 61.3%/99.78% 307.10 for C14H17N3O3S/ 308.1 (M + 1) δ 8.49-8.42 (m, 1H),8.17 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 3.9 Hz 1H), 6.84 (d, J = 3.9 Hz,1H), 3.74 (s, 3H), 3.69-3.47 (m, 2H), 1.67-1.45 (m, 6H). MF-DH- 312

 46.4%/99.99% 383.13 for C20H21N3O3S/ 384.1 (M + 1) δ 8.39-8.35 (m, 1H),8.08 (d, J = 1.8 Hz, 1H), 8.04-7.95 (m, 3H), 7.43 (br d, J = 8.1 Hz,2H), 6.86 (d, J = 4.0 Hz, 1H), 3.69-3.49 (m, 2H), 3.44-3.32 (m, 2H),2.34 (s, 3H), 1.65-1.42 (m, 6H). MF-DH- 318

 34.1%/97.63% 345.16 for C20H19N5O/ 346.2 (M + 1) δ 9.19 (s, 1H), 8.36(d, J = 1.9 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 8.09 (s, 1H), 8.06-7.98(m, 1H), 7.77-7.66 (m, 3H), 6.85-6.82 (m, 1H), 3.78-3.36 (m, 4H), 1.69-1.48 (m, 6H). MF-DH- 320

 3.5%/99.12% 320.16 for C19H20N4O/ 321.2 (M + 1) δ 8.95 (s, 1H),8.44-8.35 (m, 2H), 8.21-8.08 (m, 3H), 6.84 (d, J = 3.7 Hz, 1H),3.64-3.37 (m, 4H), 2.42 (s, 3H), 1.68-1.50 (m, 6H). MF-DH- 342

 43.6/99.48% 348.14 for C20H17FN4O/ 349.0 (M + 1) δ 8.43 (d, J = 2.0 Hz,1H), 8.34- 8.25 (m, 2H), 8.23-8.18 (m, 2H), 8.08-8.02 (m, 2H), 6.89 (d,J = 3.8 Hz, 1H), 5.02-4.84 (m, 1H), 3.84-3.39 (m, 4H), 2.05-1.69 (m,4H). MF-DH- 344

 39.6%/99.64% 348.14 for C20H17FN4O/ 349.2 (M + 1) δ 8.50-8.47 (m, 1H),8.44-8.42 (m, 1H), 8.39-8.55 (m, 1H), 8.22- 8.16 (m, 2H), 7.85-7.76 (m,2H), 6.86 (d, J = 3.8 Hz, 1H), 5.03-4.84 (m, 1H), 3.77-3.36 (m, 4H),2.02-1.70 (m, 4H). MF-DH- 366

 63.9%/99.68% 349.19 for C20H23N5O/ 350.2 (M + 1) δ 8.43 (d, J = 2.4 Hz,1H), 8.29 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.92-7.86 (m,2H), 6.82-6.73 (m, 2H), 3.69-3.34 (m, 4H), 3.09 (s, 6H), 1.67-1.49 (m,6H). MF-DH- 389

 51.0%/99.81% 331.14 for C19H17N5O/ 332.2 (M + 1) δ 9.44-9.36 (m, 1H),8.70 (dd, J = 8.5, 2.1 Hz, 1H), 8.32 (s, 1H), 8.24-8.12 (m, 2H),8.12-8.04 (m, 1H), 6.84 (d, J = 3.7 Hz, 1H), 3.59-3.25 (m, 4H),1.58-1.38 (m, 6H). MF-DH- 397

 54.6%/99.77% 332.14 for C18H16N6O/ 333.2 (M + 1) δ 9.82 (s, 2H), 8.45(d, J = 1.9 Hz, 1H), 8.36 (d, J = 3.9 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H),7.00 (d, J = 3.9 Hz, 1H), 3.74-3.33 (m, 4H), 1.68-1.46 (m, 6H). MF-DH-319

 30.5%/99.93% 345.16 for C20H19N5O/ 346.1 (M + 1) δ 13.25 (br s, 1H),8.35 (s, 1H), 8.23-8.01 (m, 3H), 7.99-7.97 (m, 1H), 7.82-7.69 (m, 2H),6.81 (s, 1H), 3.72-3.42 (m, 4H), 1.71-1.42 (m, 6H). MF-DH- 337

 33.3%/98.99% 465.22 for C28H27N5O2/ 466.1 (M + 1) δ 8.31 (d, J = 1.9Hz, 1H), 8.21- 8.19 (m, 1H), 8.19-8.09 (m, 2H), 8.00 (d, J = 3.5 Hz,1H), 7.87 (d, J = 9.0 Hz, 1H), 7.83-7.74 (m, 1H), 7.27-7.22 (m, 2H),6.91- 6.86 (m, 2H), 6.80-6.77 (m, 1H), 5.65 (s, 2H), 3.70 (s, 3H), 3.64-3.34 (m, 4H), 1.68-1.45 (m, 6H). MF-DH- 340

 34.1%/99.35% 465.22 for C28H27N5O2/ 466.2 (M + 1) δ 8.55 (s, 1H), 8.32(s, 1H), 8.10 (br d, J = 14.5 Hz, 2H), 8.06- 7.93 (m, 1H), 7.76 (br d, J= 9.2 Hz, 1H), 7.72-7.63 (m, 1H), 7.33 (br d, J = 8.4 Hz, 2H), 6.93 (brd, J = 8.4 Hz, 2H), 6.88-6.73 (m, 1H), 5.61 (s, 2H), 3.73 (s, 3H),3.66-3.37 (m, 4H), 1.69-1.47 (m, 6H). MF-DH- 343

 27.5%/98.89% 366.15 for C20H19FN4O2/ 367.1 (M + 1) δ 8.42 (d, J = 2.0Hz, 1H), 8.22- 8.11 (m, 2H), 8.06 (s, 5H), 7.43- 7.40 (m, 1H), 6.86-6.83(m, 1H), 5.03-4.84 (m, 1H), 3.75-3.36 (m, 4H), 2.03-1.85 (m, 2H), 1.84-1.69 (m, 2H). MF-DH- 345

 21.4%/99.38% 366.15 for C20H19FN4O2/ 367.1 (M + 1) δ 8.40 (d, J = 2.0Hz, 1H), 8.31 (t, J = 1.8 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.16-8.03(m, 3H), 7.86 (s, 1H), 7.69-7.61 (m, 1H), 7.53- 7.48 (m, 1H), 6.84 (d, J= 3.6 Hz, 1H), 5.03-4.84 (m, 1H), 3.77- 3.37 (m, 4H), 2.03-1.87 (m, 2H),1.84-1.69 (m, 2H). MF-DH- 365

 20.5%/96.50% 349.15 for C19H19N5O2/ 350.2 (M + 1) δ 9.27 (brs, 1H),8.62 (brd, J = 7.1 Hz, 1H), 8.40 (br s, 1H), 8.29- 8.10 (m, 4H), 7.69(br s, 1H), 6.90 (br d, J = 3.1 Hz, 1H), 3.73- 3.40 (m, 4H), 1.68-1.50(m, 6H). MF-DH- 384

 43.6%/99.72% 350.15 for C18H18N6O2/ 351.2 (M + 1) δ 9.63 (s, 2H), 8.43(d, J = 1.7 Hz, 1H), 8.31 (d, J = 3.8 Hz, 1H), 8.28-8.23 (m, 1H),8.23-8.17 (m, 1H), 7.84 (br s, 1H), 6.95 (d, J = 3.8 Hz, 1H), 3.70-3.55(m, 4H), 1.70-1.49 (m, 6H). MF-DH- 394

 40.3%/96.60% 384.14 for C20H18F2N4O2/ 385.2 (M + 1) δ 8.45 (d, J = 2.0Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 3.8 Hz, 1H), 8.06 (s,5H), 7.43 (br s, 1H), 6.85 (d, J = 3.8 Hz, 1H), 3.78-3.52 (m, 4H), 2.08(br s, 4H). MF-DH- 347

 14.2%/99.30% 353.15 for C20H20FN3O2/ 354.2 (M + 1) δ 8.37 (d, J = 2.0Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.86-7.80(m, 2H), 7.49 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 3.6 Hz, 1H), 5.27 (t, J= 5.8 Hz, 1H), 5.02-4.83 (m, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.78-3.43(m, 4H), 2.03-1.70 (m, 4H). MF-DH- 348

 28.0%/97.73% 353.15 for C20H20FN3O2/ 354.2 (M + 1) δ 8.38 (d, J = 2.0Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 3.6 Hz, 1H), 7.81 (s,1H), 7.78- 7.68 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz,1H), 6.80 (d, J = 3.8 Hz, 1H), 5.43- 5.13 (m, 1H), 5.03-4.85 (m, 1H),4.61 (s, 2H), 3.71-3.38 (m, 4H), 2.04-1.85 (m, 2H), 1.84-1.67 (m, 2H).MF-DH- 370

 63.0%/99.30% 353.13 for C20H20FN3O2/ 354.2 (M + 1) δ 8.37 (d, J = 2.0Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.86-7.80(m, 2H), 7.49 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 3.6 Hz, 1H), 5.27 (t, J= 5.8 Hz, 1H), 5.02-4.83 (m, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.78-3.43(m, 4H), 2.03-1.70 (m, 4H). MF-DH- 371

 34.6%/95.05% 363.19 for C22H25N3O2/ 364.2 (M + 1) δ 8.32 (d, J = 2.0Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.81-7.72(m, 2H), 7.68-7.58 (m, 2H), 6.78 (d, J = 3.6 Hz, 1H), 5.10 (s, 1H),3.64- 3.33 (m, 4H), 1.68-1.51 (m, 6H), 1.49 (s, 6H). MF-DH- 374

 56.3%/97.83% 353.15 for C20H20FN3O2/ 354.2 (M + 1) δ 8.38 (d, J = 2.0Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 3.6 Hz, 1H), 7.81 (s,1H), 7.78- 7.68 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz,1H), 6.80 (d, J = 3.8 Hz, 1H), 5.43- 5.13 (m, 1H), 5.03-4.85 (m, 1H),4.61 (s, 2H), 3.71-3.38 (m, 4H), 2.04-1.85 (m, 2H), 1.84-1.67 (m, 2H).MF-DH- 375

38.65%/96.62% 363.19 for C22H25N3O2/ 364.1 (M + 1) δ 8.32 (d, J = 2.0Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 3.8 Hz, 1H), 7.90-7.84(m, 1H), 7.76-7.65 (m, 1H), 7.52-7.43 (m, 2H), 6.79 (d, J = 3.6 Hz, 1H),5.13 (s, 1H), 3.66-3.35 (m, 4H), 1.67-1.51 (m, 6H), 1.49 (s, 6H). MF-DH-324

 14.6%/99.78% 403.15 for C21H30F3N3O2/ 404.1 (M + 1) δ 8.34 (d, J = 2.0Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.76-7.71(m, 2H), 7.14-7.09 (m, 2H), 6.76 (d, J = 3.6 Hz, 1H), 4.65-4.27 (m, 1H),3.83 (s, 3H), 3.14-2.78 (m, 2H), 2.71-2.55 (m, 2H), 1.93-1.77 (m, 2H),1.53-1.41 (m, 2H). MF-DH- 325

 32.0%/99.14% 411.19 for C26H25N3O2/ 412.1 (M + 1) δ 8.38 (d, J = 2.0Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.78-7.71(m, 2H), 7.34-7.27 (m, 4H), 7.27-7.17 (m, 1H), 7.16-7.08 (m, 2H), 6.77-6.76 (m, 1H), 4.82-4.38 (m, 1H), 3.83 (s, 3H), 3.20-2.89 (m, 2H),2.88-2.58 (m, 2H), 1.92- 1.62 (m, 4H). MF-DH- 326

 24.5%/98.96% 383.16 for C24H21N3O2/ 384.1 (M + 1) δ 8.62 (d, J = 2.0Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.77-7.70(m, 2H), 7.45-7.35 (m, 4H), 7.35-7.23 (m, 1H), 7.16-7.08 (m, 2H), 6.79(d, J = 3.8 Hz, 1H), 4.82-4.39 (m, 3H), 4.13-3.91 (m, 2H), 3.83 (s, 3H).MF-DH- 327

 21.2%/99.33% 418.16 for C21H21F3N4O2/ 419.2 (M + 1) δ 8.33 (d, J = 2.0Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.78-7.69(m, 2H), 7.16-7.08 (m, 2H), 6.76 (d, J = 3.6 Hz, 1H), 3.83 (s, 3H),3.66- 3.39 (m, 4H), 3.26-3.22 (m, 2H), 2.71-2.62 (m, 4H). MF-DH- 328

 11.2%/91.01% 363.19 for C22H25N3O2/ 364.1 (M + 1) δ 8.26 (d, J = 2.0Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 3.6 Hz, 1H), 7.79-7.68(m, 2H), 7.17-7.06 (m, 2H), 6.74 (d, J = 3.6 Hz, 1H), 4.66-4.17 (m, 2H),3.83 (s, 3H), 1.91-1.77 (m, 1H), 1.71-1.61 (m, 2H), 1.58-1.32 (m, 3H),1.27-1.09 (m, 7H). MF-DH- 329 (Cis)

 54.6%/98.52% 363.19 for C22H25N3O2/ 364.1 (M + 1) δ 8.31 (d, J = 2.0Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.78-7.70(m, 2H), 7.16-7.07 (m, 2H), 6.76 (d, J = 3.6 Hz, 1H), 4.56-4.34 (m, 1H),3.83 (s, 3H), 3.73-3.51 (m, 1H), 2.77-2.57 (m, 1H), 2.38-2.16 (m, 1H),1.80 (br d, J = 12.8 Hz, 1H), 1.68-1.56 (m, 2H), 0.95- 0.66 (m, 7H).MF-DH- 367

 7.34%/98.31% 406.20 for C23H26N4O3/ 407.3 (M + 1) δ 8.58 (br s, 1H),8.35 (d, J = 1.7 Hz, 1H), 8.15-7.99 (m, 6H), 6.82 (d, J = 3.7 Hz, 1H),3.61-3.38 (m, 8H), 3.27 (s, 3H), 1.66-1.46 (m, 6H). MF-DH- 368

 24.2%/99.85% 362.17 for C21H22N4O2/ 363.2 (M + 1) δ 8.51 (br d, J = 4.5Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.15-7.99 (m, 6H), 6.84 (d, J = 3.7Hz, 1H), 3.71-3.35 (m, 4H), 2.82 (d, J = 4.4 Hz, 3H), 1.66-1.54 (m, 4H).MF-DH- 369

 18.5%/98.31% 376.19 for C22H24N4O2/ 377.2 (M + 1) δ 8.36 (d, J = 2.0Hz, 1H), 8.18- 8.06 (m, 2H), 8.06-7.97 (m, 2H), 7.60 (d, J = 8.6 Hz,2H), 6.83 (d, J = 3.8 Hz, 1H), 3.68-3.35 (m, 4H), 3.04-2.96 (m, 6H),1.67- 1.49 (m, 6H). MF-DH- 285

 43.4%/99.84% 353.15 for C20H20FN3O2/ 354.2 (M + 1) δ 8.36-8.34 (m, 1H),8.16-8.14 (m, 1H), 7.95-7.92 (m, 1H), 7.76- 7.72 (m, 2H), 7.13-7.10 (m,2H), 6.77-6.75 (m, 1H), 5.01- 4.86 (m, 1H), 3.83 (s, 3H), 3.73- 3.52 (m,3H), 3.38-3.33 (m, 1H), 2.01-1.73 (m, 4H). MF-DH- 294

34.13%/98.52% 335.16 for C20H21N3O2/ 336.2 (M + 1) δ 8.34 (d, J = 1.7Hz, 1H), 8.12 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 3.7 Hz, 1H), 7.52-7.44(m, 3H), 6.98-6.94 (m, 1H), 6.80-6.78 (m, 1H), 3.84 (s, 3H), 3.66-3.37(m, 4H), 1.66-1.51 (m, 6H). MF-DH- 295

 40.2%/99.52% 340.11 for C18H17ClN4O/ 341.1 (M + 1) δ 9.23-9.21 (m, 1H),8.68-8.62 (m, 2H), 8.41-8.39 (m, 1H), 8.23- 8.15 (m, 2H), 6.90-6.87 (m,1H), 3.68-3.40 (m, 4H), 1.65- 1.52 (m, 6H). MF-DH- 296

 52.7%/97.61% 336.16 for C19H20N4O2/ 337.2 (M + 1) δ 8.81 (s, 1H),8.39-8.30 (m, 2H), 8.19-8.12 (m, 2H), 7.99 (br s, 1H), 6.85 (d, J = 3.7Hz, 1H), 3.93 (s, 3H), 3.68-3.35 (m, 4H), 1.68-1.47 (m, 6H). MF-DH- 297

 45.8%/99.26% 335.16 for C20H21N3O2/ 336.1 (M + 1) δ 8.31 (d, J = 1.6Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 3.5 Hz, 1H), 7.74 (br d,J = 8.8 Hz, 2H), 7.11 (br d, J = 8.9 Hz, 2H), 6.75 (d, J = 3.5 Hz, 1H),3.83 (s, 3H), 3.65-3.35 (m, 4H), 1.68-1.48 (m, 6H). MF-DH- 298

 31.4%/99.99% 330.15 for C20H18N4O/ 331.1 (M + 1) δ 8.42-8.36 (m, 1H),8.33-8.25 (m, J = 8.7 Hz, 2H), 8.23-8.13 (m, 2H), 8.04 (br d, J = 8.6Hz, 2H), 6.88 (d, J = 3.7 Hz, 1H), 3.70-3.34 (m, 4H), 1.67-1.47 (m, 6H).MF-DH- 300

 61.4%/99.46% 330.15 for C20H18N4O/ 331.1 (M + 1) δ 8.48 (s, 1H),8.42-8.33 (m, 2H), 8.19-8.12 (m, 2H), 7.86- 7.74 (m, 2H), 6.85 (d, J =3.8 Hz, 1H), 3.67-3.35 (m, 4H), 1.68- 1.48 (m, 6H). MF-DH- 302

 57.5%/99.57% 348.45 for C21H24N4O/ 349.2 (M + 1) δ 8.32 (d, J = 2.0 Hz,1H), 8.10 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 3.6 Hz, 1H), 7.36-7.29 (m,1H), 7.16-7.08 (m, 2H), 6.78-6.71 (m, 2H), 3.66-3.34 (m, 4H), 2.97 (s,6H), 1.67-1.49 (m, 6H). MF-DH- 305

 18.4%/99.14% 348.20 for C21H24N4O/ 349.2 (M + 1) δ 8.33-8.34 (m, 1H),8.13-8.03 (m, 1H), 7.85 (d, J = 3.4 Hz, 1H), 7.58 (br d, J = 8.9 Hz,2H), 6.87 (br d, J = 8.8 Hz, 2H), 6.72 (d, J = 3.5 Hz, 1H), 3.65-3.37(m, 4H), 2.96 (s, 6H), 1.67-1.47 (m, 6H). MF-DH- 306

 14.2%/99.73% 349.18 for C21H23N3O2/ 350.2 (M + 1) δ 8.31 (d, J = 2.0Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.72 (d, J= 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 3.6 Hz, 1H), 4.10(d, J = 7.0 Hz, 2H), 3.63-3.36 (m, 4H), 1.68- 1.48 (m, 6H), 1.39-1.34(m, 3H). MF-DH- 309

 68.3%/99.16% 383.13 for C20H21N3O3S/ 384.2 (M + 1) δ 8.50 (t, J = 1.8Hz, 1H), 8.40- 8.30 (m, 2H), 8.21-8.14 (m, 2H), 7.94-7.83 (m, 2H), 6.87(d, J = 3.8 Hz, 2H), 3.70-3.34 (m, 4H), 3.32 (s, 3H), 1.67-1.46 (m, 6H).MF-DH- 310

 57.3%/99.25% 383.13 for C20H21N3O3S/ 384.1 (M + 1) δ 8.39 (d, J = 2.0Hz, 1H), 8.33- 8.27 (m, 2H), 8.21-8.08 (m, 4H), 6.88 (d, J = 3.9 Hz,1H), 3.71- 3.34 (m, 4H), 3.28 (s, 3H), 1.68- 1.49 (m, 6H). MF-DH- 317

 17.5%/96.14% 321.16 for C18H19N5O/ 322.2 (M + 1) δ 8.37 (d, J = 2.0 Hz,1H), 8.12 (d, J = 2.0 Hz, 1H), 8.09-7.98 (m, 2H), 7.27 (d, J = 1.8 Hz,1H), 7.10 (dd, J = 5.8, 2.0 Hz, 1H), 6.82 (d, J = 3.9 Hz, 1H), 6.15 (s,2H), 3.67-3.34 (m, 4H), 1.68- 1.50 (m, 6H). MF-DH- 321

 11.5%/93.50% 322.14 for C18H18N4O2/ 323.1 (M + 1) δ 11.97-11.85 (m,1H), 8.30 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.85 (br d, J =3.6 Hz, 3H), 6.73 (d, J = 3.5 Hz, 1H), 6.53-6.49 (m, 1H), 3.71-3.36 (m,4H), 1.67-1.44 (m, 6H). MF-DH- 322

 21.4%/99.58% 321.16 for C18H19N5O/ 322.2 (M + 1) δ 8.33 (d, J = 2.0 Hz,1H), 8.21- 8.07 (m, 2H), 8.01-7.90 (m, 2H), 7.50 (t, J = 2.3 Hz, 1H),6.79 (d, J = 3.6 Hz, 2H), 5.63 (s, 2H), 3.66- 3.34 (m, 4H), 1.68-1.47(m, 6H). MF-DH- 323

 69.0%/99.53% 336.16 for C19H20N4O2/ 337.2 (M + 1) δ 8.60 (d, J = 2.4Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 8.9, 2.8 Hz, 1H), 8.13(d, J = 2.0 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H),6.80 (d, J = 3.6 Hz, 1H), 3.93 (s, 3H), 3.71- 3.35 (m, 4H), 1.67-1.49(m, 6H). MF-DH- 336

 35.5%/98.03% 321.16 for C18H19N5O/ 322.2 (M + 1) δ 8.36-8.17 (m, 2H),8.08 (br s, 1H), 7.87-7.79 (m, 1H), 7.79- 7.69 (m, 1H), 6.78-6.67 (m,1H), 6.59 (br d, J = 8.7 Hz, 1H), 6.15 (br s, 2H), 3.75-3.35 (m, 4H),1.71-1.40 (m, 6H). MF-DH- 299

 42.2%/99.76% 348.16 for C20H20N4O2/ 349.2 (M + 1) δ 8.37 (d, J = 2.0Hz, 1H), 8.18- 8.10 (m, 2H), 8.06 (s, 5H), 7.42 (br s, 1H), 6.84 (d, J =3.8 Hz, 1H), 3.70-3.33 (m, 4H), 1.68- 1.47 (m, 6H). MF-DH- 301

 47.4%/99.94% 348.16 for C20H20N4O2/ 349.1 (M + 1) δ 8.39-8.28 (m, 2H),8.18-8.03 (m, 4H), 7.87 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H),7.50 (br s, 1H), 6.83 (d, J = 3.8 Hz, 1H), 3.68-3.34 (m, 4H), 1.67-1.48(m, 6H). MF-DH- 303

 8.4%/98.61% 334.18 for C20H22N4O/ 335.2 (M + 1) δ 8.33 (s, 1H),8.13-8.11 (m, 1H), 8.00-7.98 (m, 1H), 7.79 (s, 1H), 7.73 (br d, J = 7.5Hz, 1H), 7.50-7.46 (m, 1H), 7.36-7.32 (m, 1H), 6.80-6.78 (m, 1H), 3.81(s, 2H), 3.66-3.38 (m, 4H), 1.66- 1.52 (m, 6H). MF-DH- 304

 9.6%/95.06% 334.18 for C20H22N4O/ 335.1 (M + 1) δ 8.33-8.32 (m, 1H),8.12-8.11 (m, 1H), 8.01-7.99 (m, 1H), 7.82 (br d, J = 8.7 Hz, 2H),7.54-7.50 (m, 2H), 6.79-6.77 (m, 1H), 3.83- 3.82 (m, 2H), 3.61-3.42 (m,4H), 1.65-1.53 (m, 6H). MF-DH- 307

 36.6%/99.38% 335.16 for C20H21N3O2/ 336.2 (M + 1) δ 8.33 (d, J = 2.0Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 3.8 Hz, 1H), 7.83 (d, J= 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 3.6 Hz, 1H), 5.27(t, J = 5.7 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.68-3.33 (m, 4H), 1.67-1.48 (m, 6H). MF-DH- 308

 70.4%/97.68% 335.16 for C20H21N3O2/ 336.2 (M + 1) δ 8.34 (d, J = 1.8Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.81 (s,1H), 7.78- 7.68 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.43-7.22 (m, 1H),6.79 (d, J = 3.5 Hz, 1H), 5.32 (t, J = 5.8 Hz, 1H), 4.61 (d, J = 5.8 Hz,2H), 3.75-3.35 (m, 4H), 1.75-1.35 (m, 6H). MF-DH- 191

 67.5%/95.24% 387.11 for C20H19ClFN3O2/ 388.0 (M + 1) δ 8.43 (d, J =1.71 Hz, 1H), 8.22 (s, 1H), 8.10 (d, J = 1.83 Hz, 1H), 7.72 (br d, J =8.93 Hz, 2H), 7.12 (br d, J = 8.93 Hz, 2H), 5.03-4.83 (m, 1H), 3.83 (s,3H), 3.75-3.38 (m, 4H), 2.02-1.69 (m, 4H). MF-DH- 239

 11.5%/99.59% 369.12 for C17H22FN3O/ 370.1 (M + 1) δ 8.41-8.01 (m, 3H),7.72 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H),3.71-3.33 (m, 4H), 1.68-1.46 (m, 6H). MF-DH- 250

 27.0%/98.63% 437.08 for C20H15ClF3N3O3/ 438.0 (M + 1) δ 8.47 (d, J =1.8 Hz, 1H), 8.31 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.1Hz, 1H), 7.74- 7.70 (m, 1H), 7.64-7.61 (m, 1H), 5.02-4.84 (m, 1H),3.88-3.39 (m, 4H), 2.02-1.69 (m, 4H). MF-DH- 251

 31.6%/99.67% 419.08 for C20H16ClF2N3O3/ 420.1 (M + 1) δ 8.43 (d, J =1.8 Hz, 1H), 8.30 (s, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 2.2Hz, 1H), 7.72 (dd, J = 8.7, 2.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H),3.69-3.33 (m, 4H), 1.68-1.46 (m, 6H). MF-DH- 273

 42.8%/99.80% 369.12 for C20H20ClN3O2/ 370.1 (M + 1) δ 8.43 (s, 1H),8.34 (s, 1H), 8.08- 8.03 (m, 1H), 7.52-7.43 (m, 3H), 7.02-6.95 (m, 1H),3.84 (s, 3H), 3.68-3.33 (m, 4H), 1.68-1.45 (m, 6H). MF-DH- 274

 57.2%/99.89% 374.07 for C18H16Cl2N4O/ 375.0 (M + 1) δ 9.18 (d, J = 2.1Hz, 1H), 8.68- 8.61 (m, 2H), 8.49 (s, 2H), 8.11 (d, J = 1.7 Hz, 1H),3.71-3.33 (m, 4H), 1.68-1.48 (m, 6H). MF-DH- 275

 43.3%/99.42% 370.12 for C19H19ClN4O2/ 371.1 (M + 1) δ 8.80-8.79 (m,1H), 8.47-8.43 (m, 2H), 8.35-8.33 (m, 1H), 8.10- 8.08 (m, 1H), 7.97-7.95(m, 1H), 3.93 (s, 3H), 3.68-3.57 (m, 1H), 3.33-3.33 (s, 3H), 1.67-1.51(m, 6H). MF-DH- 146

11.23%/99.67% 359.09 for C17H15ClFN5O/ 360.3 (M + 1) δ 10.00 (s, 1H),8.66 (s, 2H), 8.50- 8.44 (m, 2H), 6.98 (d, J = 3.8 Hz, 1H), 5.04-4.84(m, 1H), 3.86- 3.69 (m, 2H), 3.45-3.36 (m, 1H), 3.27-3.19 (m, 1H), 2.06-1.81 (m, 3H), 1.76-1.63 (m, 1H). MF-DH- 147

 7.5%/94.04% 393.06 for C17H14Cl2FN5O/ 394.0 (M + 1) δ 9.90 (s, 1H),8.68 (s, 2H), 8.61 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 5.04-4.86 (m, 1H),3.87-3.73 (m, 2H), 3.43-3.36 (m, 1H), 3.24- 3.18 (m, 1H), 2.04-1.84 (m,3H), 1.75-1.66 (m, 1H). MF-DH- 148

 22.4%/99.72% 339.15 for C18H18FN5O/ 340.1 (M + 1) δ 10.18 (s, 1H),8.62-8.59 (m, 2H), 8.31 (d, J = 3.8 Hz, 1H), 8.02 (s, 1H), 6.84 (d, J =3.8 Hz, 1H), 5.02-4.84 (m, 1H), 3.90- 3.65 (m, 2H), 3.41-3.34 (m, 1H),3.21-3.14 (m, 1H), 2.57-2.56 (m, 3H), 2.05-1.76 (m, 4H). MF-DH- 149

 11.2%/99.40% 373.11 for C18H17ClFN5O/ 374.0 (M + 1) δ 10.10 (s, 1H),8.63 (s, 2H), 8.47- 8.45 (m, 1H), 8.05-8.03 (m, 1H), 5.02-4.84 (m, 1H),3.89- 3.66 (m, 2H), 3.37-3.34 (m, 1H), 3.21-3.15 (m, 1H), 2.59 (s, 3H),2.02-1.68 (m, 4H). MF- PGDH-020

 13.7%/99.94% 340.11 for C18H17ClN4O/ 341.0 (M + 1) δ 9.11 (s, 1H), 8.51(d, 1H), 8.30 (d, 1H), 8.20-8.22 (m, 1H), 8.01- 8.03 (m, 1H), 7.70-7.72(m, 1H), 7.57-7.59 (m, 1H), 3.54-3.67 (m, 2H), 3.34-3.42 (m, 2H),1.48-1.68 (m, 6H). MF- PGDH-077

 14.8%/99.66% 336.16 for C19H20N4O2/ 337.2 (M + 1) δ 8.89 (s, 1H), 8.43(d, J = 1.83 Hz, 1H), 8.20 (d, J = 1.96 Hz, 1H), 7.78-7.82 (m, 2H),7.15-7.19 (m, 2H), 3.84 (s, 3H), 3.54-3.68 (m, 2H), 3.34-3.45 (m, 2H),1.49-1.67 (m, 6H). MF- PGDH-078

  15%/99.73% 354.15 for C19H19FN4O2/ 355.2 (M + 1) δ 8.90 (s, 1H),8.47-8.48 (d, J = 1.83 Hz, 1H), 8.25-8.26 (d, J = 1.96 Hz, 1H),7.79-7.81 (m, 2H), 7.13-7.15 (m, 2H), 4.82-5.01 (m, 1H), 3.84-3.85 (s,3H), 3.52- 3.80 (m, 4H), 1.83-2.01 (m, 2H), 1.71-1.82 (m, 2H). MF-PGDH-079

 5.5%/98.59% 372.14 for C19H18F2N4O2/ 373.2 (M + 1) δ 8.90 (s, 1H),8.50-8.51 (d, J = 1.83 Hz, 1H), 8.30-8.31 (d, J = 1.96 Hz, 1H),7.79-7.81 (m, 2H), 7.16-7.18 (m, 2H), 3.84-3.85 (s, 3H), 3.55-3.70 (m,4H), 2.03- 2.12 (m, 4H). MF-DH- 201

  18%/99.77% 318.19 for C17H23FN4O/ 319.3 (M + 1) δ 8.65-8.63 (m, 1H),8.41 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 5.02-4.83 (m, 1H),4.51- 4.42 (m, 1H), 3.76-3.45 (m, 4H), 2.11-1.92 (m, 6H), 1.83-1.71 (m,2H), 0.73-0.68 (m, 6H). MF-DH- 214

 18.7%/97.08% 342.13 for C18H16F2N4O/ 343.1 (M + 1) δ 8.97-8.96 (m, 1H),8.50-8.48 (m, 1H), 8.29-8.27 (m, 1H), 8.01- 7.96 (m, 2H), 7.51-7.46 (m,2H), 5.03-4.84 (m, 1H), 3.76- 3.48 (m, 4H), 2.02-1.76 (m, 4H). MF-DH-215

  19%/98.20% 324.14 for C18H17FN4O/ 325.1 (M + 1) δ 8.97-8.95 (m, 1H),8.46-8.44 (m, 1H), 8.24-8.21 (m, 1H), 8.01- 7.95 (m, 2H), 7.51-7.46 (m,2H), 3.69-3.38 (m, 4H), 1.67- 1.50 (m, 6H). MF-DH- 216

19.15%/99.63% 360.12 for C18H15F3N4O/ 361.2 (M + 1) δ 9.03-9.00 (m, 1H),8.52 (d, J = 1.7 Hz, 1H), 8.30-8.28 (m, 1H), 8.22-8.16 (m, 1H),7.92-7.87 (m, 1H), 7.77-7.69 (m, 1H), 5.02- 4.84 (m, 1H), 3.76-3.43 (m,4H), 2.02-1.76 (m, 4H). MF-DH- 217

20.74%/98.35% 342.13 for C18H16F2N4O/ 343.1 (M + 1) δ 9.02-9.00 (m, 1H),8.48 (d, J = 1.7 Hz, 1H), 8.24 (d, J = 1.8 Hz, 2H), 7.93-7.87 (m, 1H),7.78- 7.69 (m, 1H), 3.72-3.52 (m, 2H), 3.49-3.33 (m, 2H), 1.67-1.52 (m,6H). MF-DH- 218

  12%/87.77% 408.12 for C19H16F4N4O2/ 409.2 (M + 1) δ 9.04-9.02 (m, 1H),8.52-8.50 (m, 1H), 8.31-8.29 (m, 1H), 8.13- 8.10 (m, 2H), 7.68-7.64 (m,2H), 5.04-4.84 (m, 1H), 3.80- 3.54 (m, 4H), 2.00-1.76 (m, 4H). MF-DH-219

  18%/97.93% 390.13 for C19H17F3N4O2/ 391.1 (M + 1) δ 9.04-9.00 (m, 1H),8.48-8.45 (m, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.11 (br d, J = 8.9 Hz,2H), 7.65 (brd, J = 8.3 Hz, 2H), 3.75-3.40 (m, 4H), 1.67-1.51 (m, 6H).MF-DH- 222

 14.2%/99.99% 390.13 for C19H17F3N4O2/ 391.1 (M + 1) δ 8.99-8.98 (m,1H), 8.50 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.02-7.98 (m,2H), 7.54- 7.34 (m, 3H), 5.03-4.84 (m, 1H), 3.79-3.47 (m, 4H), 2.04-1.76(m, 4H). MF-DH- 223

 16.6%/99.68% 372.14 for C19H17F3N4O2/ 373.1 (M + 1) δ 8.99-8.95 (m,1H), 8.47-8.44 (m, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.02-7.99 (m, 1H),7.54-7.32 (m, 3H), 3.74-3.33 (m, 4H), 1.67- 1.49 (m, 6H). MF-DH- 224

 28.5%/99.38% 366.13 for C20H16F2N4O/ 367.2 (M + 1) δ 8.91-8.87 (m, 1H),8.50-8.44 (m, 1H), 8.25 (d, J = 1.7 Hz, 1H), 7.79 (br d, J = 8.8 Hz,2H), 7.15 (br d, J = 8.9 Hz, 2H), 5.03-4.84 (m, 1H), 4.16-4.08 (m, 2H),3.80- 3.40 (m, 4H), 2.03-1.89 (m, 2H), 1.83-1.70 (m, 2H), 1.37 (br t, J= 6.9 Hz, 3H). MF-DH- 225

 24.2%/97.80% 350.17 for C20H22N4O2/ 351.2 (M + 1) δ 8.90-8.85 (m, 1H),8.43 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 1.7 Hz, 1H), 7.79 (d, J = 8.9 Hz,2H), 7.15 (d, J = 8.9 Hz, 2H), 4.12 (q, J = 6.9 Hz, 2H), 3.70-3.54 (m,2H), 3.49-3.34 (m, 2H), 1.67- 1.49 (m, 6H), 1.37 (t, J = 7.0 Hz, 3H).MF-DH- 226

15.07%/97.09% 408.12 for C19H16F4N4O2/ 409.1 (M + 1) δ 9.10-9.07 (m,1H), 8.55-8.52 (m, 1H), 8.32-8.29 (m, 1H), 8.15- 8.12 (m, 1H), 8.09 (brd, J = 7.7 Hz, 1H), 7.80-7.74 (m, 1H), 7.53- 7.48 (m, 1H), 5.03-4.84 (m,1H), 3.81-3.40 (m, 4H), 2.03- 1.73 (m, 4H). MF-DH- 227

11.61%/98.05% 390.13 for C19H17F3N4O2/ 391.1 (M + 1) δ 9.09-9.07 (m,1H), 8.50-8.48 (m, 1H), 8.26-8.23 (m, 1H), 8.15- 8.12 (m, 1H), 8.10-8.06(m, 1H), 7.80-7.74 (m, 1H), 7.53- 7.47 (m, 1H), 3.78-3.50 (m, 4H),1.69-1.53 (m, 6H). MF-DH- 228

 29.1%/98.28% 390.13 for C19H17F3N4O2/ 391.1 (M + 1) δ 9.07-9.04 (m,1H), 8.53-8.51 (m, 1H), 8.30-8.28 (m, 1H), 7.93- 7.88 (m, 2H), 7.71-7.65(m, 1H), 7.56-7.18 (m, 2H), 5.03- 4.84 (m, 1H), 3.80-3.39 (m, 4H),2.03-1.72 (m, 4H). MF-DH- 229

 5.3%/95.11% 372.14 for C19H18F2N4O2/ 373.1 (M + 1) δ 9.06-9.03 (m, 1H),8.48 (d, J = 1.7 Hz, 1H), 8.23 (d, J = 1.7 Hz, 1H), 7.93-7.87 (m, 2H),7.68 (s, 1H), 7.57-7.17 (m, 2H), 3.70- 3.35 (m, 4H), 1.67-1.51 (m, 6H).MF-DH- 236

 47.3%/99.81% 300.20 for C17H24N4O/ 301.2 (M + 1) δ 8.65-8.62 (m, 1H),8.37 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 1.7 Hz, 1H), 4.52-4.42 (m, 1H),3.72- 3.35 (m, 4H), 2.13-1.91 (m, 4H), 1.66-1.49 (m, 6H), 0.73-0.67 (m,6H). MF-DH- 238

  15%/99.77% 340.13 for C18H17FN4O2/ 341.2 (M + 1) δ 9.83-9.81 (m, 1H),8.82 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.64(d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.03-4.88 (m, 1H), 3.80-3.40 (m, 4H), 2.01-1.75 (m, 4H). MF-DH- 442

28.77%/97.51% 367.12 for C19H15F2N5O/ 368.2 (M + 1) δ 9.17 (s, 1H), 8.58(d, J = 1.7 Hz, 1H), 8.38-8.36 (m, 1H), 8.36- 8.28 (m, J = 8.8 Hz, 2H),8.13 (d, J = 8.7 Hz, 2H), 3.84-3.44 (m, 4H), 2.16-2.01 (m, 4H). MF-DH-443

31.25%/98.35% 337.07 for C17H12ClN5O/ 338.1 (M + 1) δ 9.18 (s, 1H), 8.75(d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H),8.13 (d, J = 8.7 Hz, 2H), 4.89 (br s, 2H), 4.73-4.51 (m, 2H), 4.16 (brs, 1H). MF-DH- 464

 67.3%/99.47% 385.14 for C19H17F2N5O2/ 386.2 (M + 1) δ 9.10 (s, 1H),8.56 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.11 (s, 5H), 7.49(br s, 1H), 3.86- 3.42 (m, 4H), 2.17-2.00 (m, 4H). MF-DH- 176

 9.37%/99.23% 368.16 for C20H21FN4O2/ 369.1 (M + 1) δ 8.29-8.26 (m, 1H),8.08-8.06 (m, 1H), 7.50-7.45 (m, 2H), 7.17- 7.13 (m, 2H), 5.00-4.85 (m,1H), 3.87-3.84 (m, 3H), 3.80- 3.36 (m, 4H), 2.46 (s, 3H), 2.01- 1.71 (m,4H). MF-DH- 205

20.79%/99.72% 350.17 for C20H22N4O2/ 351.1 (M + 1) δ 8.25-8.22 (m, 1H),8.01 (s, 1H), 7.48 (br d, J = 8.7 Hz, 2H), 7.15 (br d, J = 8.8 Hz, 2H),3.86 (s, 3H), 3.69-3.51 (m, 2H), 3.43- 3.34 (m, 2H), 2.46 (br s, 3H),1.67-1.49 (m, 6H). MF-DH- 117

 28.6%/97.00% 439.20 for C23H26FN5O3/ 440.1 (M + 1) δ 8.30-8.27 (m, 1H),8.12 (d, J = 1.7 Hz, 1H), 7.96-7.91 (m, 1H), 7.46 (br d, J = 8.8 Hz,2H), 7.15 (br d, J = 8.9 Hz, 2H), 5.03-4.84 (m, 1H), 3.89-3.84 (m, 3H),3.76- 3.44 (m, 6H), 2.89 (br t, J = 7.0 Hz, 2H), 2.02-1.85 (m, 2H),1.80- 1.70 (m, 5H). MF-DH- 130

  40%/98.58% 393.16 for C20H22N4O2/ 391.8 (M − 1) δ 8.37-8.35 (m, 1H),8.24 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.18-7.15 (m, 2H),5.02- 4.84 (m, 1H), 4.41 (s, 2H), 3.87- 3.85 (m, 3H), 3.78-3.51 (m, 4H),1.99-1.76 (m, 4H). MF-DH- 184

  27%/97.46% 382.18 for C21H23N3O2/ 383.1 (M + 1) δ 8.29-8.26 (m, 1H),8.10 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz,2H), 5.02-4.83 (m, 1H), 3.86 (s, 3H), 3.74-3.47 (m, 4H), 2.81-2.74 (m,2H), 2.01-1.75 (m, 4H), 1.28- 1.25 (m, 3H). MF-DH- 185

 1.96%/91.31% 412.19 for C22H25FN4O3/ 413.1 (M + 1) δ 8.32-8.29 (m, 1H),8.13-8.10 (m, 1H), 7.49-7.44 (m, 2H), 7.18- 7.14 (m, 2H), 5.03-4.48 (m,1H), 3.87-3.85 (m, 3H), 3.73- 3.71 (m, 4H), 3.21-3.18 (m, 3H), 3.04-2.99(m, 2H), 2.01-1.72 (m, 6H). MF-DH- 195

  26%/99.27% 450.17 for C22H22F4N4O2/ 451.1 (M + 1) δ 8.34-8.30 (m, 1H),8.15 (s, 1H), 7.50 (br d, J = 8.6 Hz, 2H), 7.17 (br d, J = 8.7 Hz, 2H),5.02- 4.83 (m, 1H), 3.88-3.85 (m, 3H), 3.74-3.47 (m, 4H), 3.06-3.00 (m,2H), 2.93-2.79 (m, 2H), 2.02- 1.76 (m, 4H). MF-DH- 267

  10%/93.70% 394.20 for C22H26N4O3/ 395.2 (M + 1) δ 8.26-8.23 (m, 1H),8.05 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz,2H), 3.86 (s, 3H), 3.76-3.71 (m, 2H), 3.66-3.44 (m, 3H), 3.19 (s, 3H),3.04-2.98 (m, 2H), 1.66-1.46 (m, 7H). MF-DH- 268

  22%/98.27% 432.18 for C22H23F3N4O2/ 433.1 (M + 1) δ 8.28 (s, 1H), 8.09(s, 1H), 7.56- 7.46 (m, 2H), 7.21-7.11 (m, 2H), 3.86 (s, 3H), 3.72-3.59(m, 2H), 3.46-3.44 (m, 2H), 3.09- 2.98 (m, 2H), 2.94-2.88 (m, 2H),1.66-1.46 (m, 6H). MF-DH- 337

 32.7%/98.99% 465.22 for C28H27N5O2/ 466.1 (M + 1) δ 8.31 (d, J = 1.9Hz, 1H), 8.21- 8.19 (m, 1H), 8.19-8.09 (m, 2H), 8.00 (d, J = 3.5 Hz,1H), 7.87 (d, J = 9.0 Hz, 1H), 7.83-7.74 (m, 1H), 7.27-7.22 (m, 2H),6.91- 6.86 (m, 2H), 6.80-6.77 (m, 1H), 5.65 (s, 2H), 3.70 (s, 3H), 3.64-3.34 (m, 4H), 1.68-1.45 (m, 6H). MF-DH- 340

 34.2%/99.35% 465.22 for C28H27N5O2/ 466.2 (M + 1) δ 8.55 (s, 1H), 8.32(s, 1H), 8.10 (br d, J = 14.5 Hz, 2H), 8.06- 7.93 (m, 1H), 7.76 (br d, J= 9.2 Hz, 1H), 7.72-7.63 (m, 1H), 7.33 (br d, J = 8.4 Hz, 2H), 6.93 (brd, J = 8.4 Hz, 2H), 6.88-6.73 (m, 1H), 5.61 (s, 2H), 3.73 (s, 3H),3.66-3.37 (m, 4H), 1.69-1.47 (m, 6H). MF-DH- 351

 21.4%/99.26% 367.14 for C19H18FN5O2/ 368.2 (M + 1) δ 9.33-9.31 (m, 1H),9.01 (d, J = 1.6 Hz, 1H), 8.76-8.73 (m, 1H), 8.43 (d, J = 2.0 Hz, 1H),8.28 (br s, 1H), 8.23-8.19 (m, 2H), 7.76 (br s, 1H), 6.91-6.88 (m, 1H),5.03-4.84 (m, 1H), 3.76-3.56 (m, 4H), 1.99-1.75 (m, 4H). MF-DH- 355

 38.7%/90.57% 367.14 for C19H18FN5O2/ 368.2 (M + 1) δ 9.27 (d, J = 2.4Hz, 1H), 8.64- 8.59 (m, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.32-8.20 (m,3H), 8.20- 8.05 (m, 1H), 7.70 (br s, 1H), 6.91 (d, J = 3.8 Hz, 1H),5.03- 4.84 (m, 1H), 3.79-3.46 (m, 4H), 2.03-1.74 (m, 4H). MF-DH- 361

 53.1%/99.56% 349.15 for C19H19N5O2/ 350.2 (M + 1) δ 9.32 (d, J = 2.4Hz, 1H), 9.00 (d, J = 1.7 Hz, 1H), 8.74 (t, J = 2.2 Hz, 1H), 8.39 (d, J= 2.0 Hz, 1H), 8.27 (br s, 1H), 8.22-8.15 (m, 2H), 7.78-7.73 (m, 1H),6.89 (d, J = 3.8 Hz, 1H), 3.71-3.37 (m, 4H), 1.68-1.50 (m, 6H). MF-DH-362

 46.6%/95.07% 363.17 for C20H21N5O2/ 364.2 (M + 1) δ 9.32-9.29 (m, 1H),8.96 (d, J = 1.9 Hz, 1H), 8.75 (br d, J = 4.6 Hz, 1H), 8.72 (t, J = 2.2Hz, 1H), 8.40-8.38 (m, 1H), 8.20-8.15 (m, 2H), 6.90-6.87 (m, 1H), 3.70-3.44 (m, 4H), 2.87-2.83 (m, 3H), 1.67-1.61 (m, 2H), 1.60- 1.48 (m, 4H).MF-DH- 363

 34.2%/98.79% 377.19 for C21H23N5O2/ 378.2 (M + 1) δ 9.33-9.18 (m, 1H),8.60 (s, 1H), 8.48 (br s, 1H), 8.43-8.34 (m, 1H), 8.26-8.12 (m, 2H),6.87 (br d, J = 3.4 Hz, 1H), 3.76-3.37 (m, 4H), 3.09-2.97 (m, 6H), 1.67-1.44 (m, 6H). MF-DH- 364

 32.7%/97.33% 331.14 for C19H17N5O/ 332.2 (M + 1) δ 9.58-9.55 (m, 1H),9.01-8.95 (m, 2H), 8.43-8.39 (m, 1H), 8.25- 8.14 (m, 2H), 6.93-6.89 (m,1H), 3.68-3.44 (m, 4H), 1.68- 1.50 (m, 6H). MF-DH- 365

 51.5%/96.50% 349.15 for C19H19N5O2/ 350.2 (M + 1) δ 9.27 (br s, 1H),8.62 (br d, J = 7.1 Hz, 1H), 8.40 (br s, 1H), 8.29- 8.10 (m, 4H), 7.69(br s, 1H), 6.90 (br d, J = 3.1 Hz, 1H), 3.73- 3.40 (m, 4H), 1.68-1.50(m, 6H). MF-DH- 366

 44.7%/99.68% 349.19 for C20H23N5O/ 350.2 (M + 1) δ 8.43 (d, J = 2.4 Hz,1H), 8.29 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.92-7.86 (m,2H), 6.82-6.73 (m, 2H), 3.69-3.34 (m, 4H), 3.09 (s, 6H), 1.67-1.49 (m,6H). MF-DH- 376

 12.5%/99.64% 348.20 for C21H24N4O/ 349.2 (M + 1) δ 8.34-8.32 (m, 1H),8.12 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 3.7 Hz, 1H), 7.82-7.72 (m, 2H),7.48 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.79 (d, J = 3.7 Hz,1H), 4.13-4.06 (m, 1H), 3.79-3.33 (m, 6H), 1.68-1.51 (m, 6H), 1.36- 1.30(m, 3H). MF-DH- 380

 38.2%/99.26% 380.16 for C21H21FN4O2/ 381.2 (M + 1) δ 8.19 (s, 1H),8.13-7.99 (m, 6H), 7.41 (br s, 1H), 6.94-6.91 (m, 1H), 5.01-4.82 (m,1H), 3.88- 3.65 (m, 2H), 3.41-3.33 (m, 1H), 3.22-3.13 (m, 1H), 2.52 (brs, 3H), 2.06-1.57 (m, 4H). MF-DH- 382

 70.1%/99.58% 400.11 for C20H18ClFN4O2/ 401.2 (M + 1) δ 8.51-8.42 (m,2H), 8.13 (s, 1H), 8.10-8.01 (m, 5H), 7.42 (s, 1H), 5.01-4.80 (m, 1H),3.81- 3.40 (m, 4H), 2.03-1.72 (m, 4H). MF-DH- 383

 39.5%/97.76% 382.12 for C20H19ClN4O2/ 383.1 (M + 1) δ 8.47-8.45 (m,1H), 8.43-8.41 (m, 1H), 8.09-8.03 (m, 6H), 7.46- 7.42 (m, 1H), 3.72-3.40(m, 4H), 1.67-1.52 (m, 6H). MF-DH- 385

 50.6%/99.68% 440.22 for C27H28N4O2/ 441.3 (M + 1) δ 7.77 (br s, 1H),7.65 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 3.8 Hz, 1H), 7.37-7.30 (m, 4H),7.30-7.17 (m, 1H), 7.11-7.00 (m, 3H), 6.72 (d, J = 3.7 Hz, 1H), 4.76 (d,J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.38 (br s, 4H), 1.60-1.42 (m, 6H).MF-DH- 387

 38.4%/99.79% 362.15 for C21H19FN4O/ 363.2 (M + 1) δ 8.29 (d, J = 8.8Hz, 2H), 8.23- 8.15 (m, 2H), 8.03 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 3.9Hz, 1H), 5.02-4.82 (m, 1H), 3.88-3.64 (m, 2H), 3.40-3.33 (m, 1H), 3.22-3.12 (m, 1H), 2.56-2.51 (m, 3H), 2.06-1.58 (m, 4H). MF-DH- 388

16.66%/99.83% 382.10 for C20H16ClFN4O/ 383.2 (M + 1) δ 8.50-8.46 (m,2H), 8.24-8.20 (m, 2H), 8.14-8.12 (m, 1H), 8.05- 8.01 (m, 2H), 4.99-4.80(m, 1H), 3.89-3.43 (m, 4H), 1.99- 1.65 (m, 4H). MF-DH- 392

 6.84%/95.06% 335.17 for C19H21N5O/ 336.2 (M + 1) δ 8.30-8.27 (m, 1H),8.08 (d, J = 1.9 Hz, 2H), 7.82 (d, J = 3.5 Hz, 1H), 7.64 (d, J = 1.9 Hz,1H), 6.73-6.71 (m, 1H), 5.94 (s, 2H), 3.60-3.43 (m, 4H), 2.13 (s, 3H),1.65-1.52 (m, 6H). MF-DH- 393

 16.5%/98.32% 355.12 for C18H18ClN5O/ 356.2 (M + 1) δ 8.33-8.30 (m, 2H),8.10 (d, J = 2.1 Hz, 2H), 7.93-7.91 (m, 1H), 6.76-6.74 (m, 1H), 6.52 (s,2H), 3.55-3.39 (m, 4H), 1.67-1.53 (m, 6H). MF-DH- 395 (Cis- relative)

 13.7%/99.97% 376.19 for C22H24N4O2/ 377.2 (M + 1) δ 8.33 (d, J = 1.9Hz, 1H), 8.14- 8.10 (m, 2H), 8.10-8.02 (m, 5H), 7.44-7.38 (m, 1H), 6.82(d, J = 3.8 Hz, 1H), 4.48-4.27 (m, 2H), 1.92-1.78 (m, 1H), 1.72-1.61 (m,2H), 1.59-1.44 (m, 3H), 1.29- 1.17 (m, 6H). MF-DH- 396

 68.1%/99.29% 381.14 for C20H17F2N5O/ 382.2 (M + 1) δ 13.26 (br s, 1H),8.41-8.40 (m, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.20-8.18 (m, 1H),8.16-8.14 (m, 1H), 8.04-8.02 (m, 1H), 7.80- 7.77 (m, 1H), 7.73-7.70 (m,1H), 6.80 (d, J = 3.6 Hz, 1H), 3.72-3.59 (m, 4H), 2.12-2.04 (m, 4H).MF-DH- 397

 68.9/99.77% 332.14 for C18H16N6O/ 333.2 (M + 1) δ 9.82 (s, 2H), 8.45(d, J = 1.9 Hz, 1H), 8.36 (d, J = 3.9 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H),7.00 (d, J = 3.9 Hz, 1H), 3.74-3.33 (m, 4H), 1.68-1.46 (m, 6H). MF-DH-399

36.05%/95.01% 363.17 for C20H21N5O2/ 364.2 (M + 1) δ 9.70 (s, 1H), 8.36(d, J = 1.8 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.12-8.04 (m, 1H),7.99-7.90 (m, J = 8.7 Hz, 2H), 7.89-7.82 (m, 2H), 6.81 (d, J = 3.7 Hz,1H), 5.89 (s, 2H), 3.68-3.37 (m, 4H), 1.68-1.50 (m, 6H). MF-DH- 400

 19.2%/92.70% 363.17 for C20H21N5O2/ 364.2 (M + 1) δ 9.75 (s, 1H), 8.34(d, J = 2.0 Hz, 1H), 8.14-8.06 (m, 3H), 7.96- 7.84 (m, 1H), 7.68 (d, J =8.0 Hz, 1H), 7.60-7.52 (m, 1H), 6.81 (d, J = 3.8 Hz, 1H), 5.93 (s, 2H),3.75- 3.40 (m, 4H), 1.69-1.51 (m, 6H). MF-DH- 402

 31.2%/99.68% 387.17 for C22H21N5O2/ 388.3 (M + 1) δ 8.22-8.18 (m, 1H),8.00-7.99 (m, 1H), 7.85-7.79 (m, 2H), 7.48- 7.43 (m, 1H), 7.26-7.23 (m,1H), 7.11-7.04 (m, 2H), 3.90 (s, 3H), 3.87-3.62 (m, 2H), 3.37 (br s,2H), 1.71 (br s, 6H). MF-DH- 403

 45.4%/98.95% 511.24 for C27H31F2N5O3/ 512.3 (M + 1) δ 8.62-8.55 (m,1H), 8.55-8.44 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 3.6 Hz,1H), 8.11- 7.98 (m, 4H), 7.62 (s, 1H), 6.85 (d, J = 3.8 Hz, 1H),3.79-3.51 (m, 4H), 3.40-3.36 (m, 2H), 3.29- 3.23 (m, 2H), 2.14-2.02 (m,4H), 1.09 (s, 9H). MF-DH- 404

 18.1%/99.02% 426.19 for C23H24F2N4O2/ 427.2 (M + 1) δ 8.45 (d, J = 2.0Hz, 1H), 8.30- 8.27 (m, 1H), 8.24-8.22 (m, 1H), 8.22-8.11 (m, 1H),8.10-7.99 (m, 4H), 6.85 (d, J = 3.8 Hz, 1H), 4.18-4.08 (m, 1H),3.76-3.50 (m, 4H), 2.15-2.01 (m, 4H), 1.21- 1.18 (m, 6H). MF-DH- 405

35.32%/99.98% 455.21 for C24H27F2N5O2/ 456.3 (M + 1) δ 9.32-9.30 (m,1H), 8.99 (d, J = 1.9 Hz, 1H), 8.72 (t, J = 2.3 Hz, 1H), 8.68-8.60 (m,1H), 8.47 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.23-8.21 (m,1H), 6.91- 6.89 (m, 1H), 3.75-3.56 (m, 4H), 3.19-3.15 (m, 2H), 2.16-2.02 (m, 4H), 0.94 (s, 9H). MF-DH- 406

 38.9%/93.87% 441.20 for C23H25F2N5O2/ 442.2 (M + 1) δ 9.28-9.26 (m,1H), 8.65-8.61 (m, 1H), 8.48-8.46 (m, 1H), 8.27- 8.19 (m, 3H), 8.05 (s,1H), 6.93- 6.91 (m, 1H), 3.81-3.53 (m, 4H), 2.16-2.01 (m, 4H), 1.44 (s,9H). MF-DH- 407

 29.2%/97.29% 455.21 for C24H27F2N5O2/ 456.3 (M + 1) δ 9.32-9.29 (m,1H), 9.00 (d, J = 1.5 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H),8.39-8.19 (m, 3H), 6.90 (d, J = 3.7 Hz, 1H), 3.89-3.79 (m, 1H),3.76-3.52 (m, 4H), 2.17-2.01 (m, 4H), 1.65- 1.47 (m, 4H), 0.92-0.87 (m,6H). MF-DH- 409

 18.3%/95.45% 505.16 for C23H25F2N5O4S/ 506.2 (M + 1) δ 8.64-8.58 (m,1H), 8.47-8.44 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.17-8.14 (m, 1H),8.12-8.02 (m, 4H), 7.20-7.15 (m, 1H), 6.87- 6.84 (m, 1H), 3.78-3.52 (m,4H), 3.45-3.38 (m, 2H), 3.19- 3.12 (m, 2H), 2.92 (s, 3H), 2.14- 2.02 (m,4H). MF-DH- 411

 49.6%/98.58% 427.18 for C22H23F2N5O2/ 428.2 (M + 1) ¹H NMR (CD₃OD): δ8.46-8.43 (m, 1H), 8.21 (d, J = 1.9 Hz, 1H), 8.11-7.99 (m, 4H), 7.93 (d,J = 3.8 Hz, 1H), 6.85 (d, J = 3.8 Hz, 1H), 3.93-3.68 (m, 4H), 3.65- 3.59(m, 2H), 3.11-3.04 (m, 2H), 2.17-2.02 (m, 4H). MF-DH- 412

 25.3%/99.18% 458.18 for C23H24F2N4O4/ 459.2 (M + 1) δ 8.46 (d, J = 2.1Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 3.7 Hz, 1H), 8.10-8.03(m, 5H), 6.86 (d, J = 3.8 Hz, 1H), 4.68 (t, J = 5.7 Hz, 2H), 4.03-3.96(m, 1H), 3.83-3.58 (m, 4H), 3.58- 3.52 (m, 4H), 2.08 (br s, 4H). MF-DH-413

 18.1%/95.26% 428.17 for C22H22F2N4O3/ 429.3 (M + 1) δ 8.56-8.50 (m,1H), 8.47-8.44 (m, 1H), 8.25-8.21 (m, 1H), 8.17- 8.13 (m, 1H), 8.10-8.02(m, 4H), 6.87-6.83 (m, 1H), 4.78- 4.73 (m, 1H), 3.71-3.52 (m, 6H),3.40-3.37 (m, 2H), 2.15-2.03 (m, 4H). MF-DH- 417 (Cis- relative)

54.34%/99.38% 366.13 for C20H16F2N4O/ 367.2 (M + 1) δ 8.43-8.38 (m, 1H),8.30 (br d, J = 8.4 Hz, 2H), 8.25-8.19 (m, 1H), 8.19-8.12 (m, 1H), 8.05(br d, J = 8.4 Hz, 2H), 6.91 (br d, J = 3.4 Hz, 1H), 5.08-4.63 (m, 3H),4.13-3.84 (m, 1H), 2.70-2.66 (m, 1H), 2.36-2.22 (m, 2H), 2.18- 1.98 (m,1H). MF-DH- 418

 48.5%/97.93% 412.17 for C22H22F2N4O2/ 413.2 (M + 1) δ 8.56-8.51 (m,1H), 8.45 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.14 (d, J =3.8 Hz, 1H), 8.10-7.99 (m, 4H), 6.85 (d, J = 3.8 Hz, 1H), 3.80-3.52 (m,4H), 3.36-3.32 (m, 2H), 2.14-2.00 (m, 4H), 1.18-1.13 (m, 3H). MF-DH- 419

19.7%/99.5% 467.21 for C25H27F2N5O2/ 468.3 (M + 1) δ 8.47-8.43 (m, 1H),8.37 (br d, J = 7.7 Hz, 1H), 8.25-8.21 (m, 1H), 8.17-8.12 (m, 1H), 8.09-8.01 (m, 4H), 6.87-6.83 (m, 1H), 3.99-3.87 (m, 1H), 3.82-3.53 (m, 4H),3.44-3.38 (m, 1H), 3.09 (br d, J = 12.1 Hz, 2H), 2.67 (br d, J = 5.3 Hz,2H), 2.14-2.03 (m, 4H), 1.88-1.80 (m, 2H), 1.58- 1.49 (m, 2H). MF-DH-420

 8.5%/98.08% 439.18 for C23H23F2N5O2/ 440.0 (M + 1) δ 8.93-8.86 (m, 1H),8.45 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 8.06(d, J = 4.0 Hz, 4H), 6.86 (d, J = 3.8 Hz, 1H), 4.78-4.68 (m, 1H),3.82-3.44 (m, 8H), 2.15-2.01 (m, 4H). MF-DH- 421

 13.7%/97.62% 516.16 for C25H26F2N4O4S/ 516.9 δ 8.51-8.47 (m, 1H),8.46-8.44 (m, 1H), 8.25-8.22 (m, 1H), 8.16- 8.13 (m, 1H), 8.10-8.03 (m,4H), 6.88-6.84 (m, 1H), 4.28- 4.20 (m, 1H), 3.84-3.37 (m, 6H), 3.20-3.09(m, 2H), 2.20-2.04 (m, 8H). MF-DH- 422

46.72%/93.38% 413.17 for C21H21F2N5O2/ 414.2 (M + 1) δ 9.28-9.26 (m,1H), 8.85-8.80 (m, 1H), 8.64-8.59 (m, 1H), 8.49- 8.45 (m, 1H), 8.28-8.19(m, 3H), 6.93-6.90 (m, 1H), 3.80- 3.52 (m, 4H), 3.41-3.34 (m, 2H),2.15-2.01 (m, 4H), 1.19-1.13 (m, 3H). MF-DH- 426

 56.5%/90.34% 399.14 for C21H19F2N3O3/ 400.0 (M + 1) δ 12.48-12.15 (m,1H), 8.42- 8.39 (m, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 3.7 Hz,1H), 7.82 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.80 (d, J =3.7 Hz, 1H), 3.78-3.51 (m, 6H), 2.15- 1.98 (m, 4H). MF-DH- 427

 31.3%/98.54% 425.16 for C23H21F2N3O3/ 426.0 (M + 1) δ 12.55-12.22 (m,1H), 8.40 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.02 (d, J =3.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 6.80(d, J = 3.5 Hz, 1H), 3.73-3.54 (m, 4H), 2.14- 2.01 (m, 4H), 1.50 (br d,J = 2.9 Hz, 2H), 1.26-1.17 (m, 2H). MF-DH- 428

21.3%/98.9% 462.12 for C21H20F2N4O4S/ 463.2 (M + 1) δ 12.27-12.14 (m,1H), 8.48 (d, J = 2.0 Hz, 1H), 8.26-8.19 (m, 4H), 8.17-8.12 (m, 2H),6.88 (d, J = 3.8 Hz, 1H), 3.80-3.53 (m, 4H), 3.42-3.40 (m, 3H), 2.08 (brs, 4H). MF-DH- 429

 27.6%/98.97% 468.16 for C24H22F2N4O4/ 406.9 (M + 1) δ 12.43-12.28 (m,1H), 9.07- 8.99 (m, 1H), 8.48-8.43 (m, 1H), 8.24-8.21 (m, 1H), 8.18-8.13(m, 1H), 8.12-8.07 (m, 2H), 8.06- 8.01 (m, 2H), 6.88-6.82 (m, 1H),3.75-3.53 (m, 4H), 2.15- 1.99 (m, 4H), 1.46-1.40 (m, 2H), 1.17-1.10 (m,2H). MF-DH- 430

 30.1%/98.97% 468.16 for C24H22F2N4O4/ 469.0 (M + 1) δ 12.43-12.28 (m,1H), 9.07- 8.99 (m, 1H), 8.48-8.43 (m, 1H), 8.24-8.21 (m, 1H), 8.18-8.13(m, 1H), 8.12-8.07 (m, 2H), 8.06- 8.01 (m, 2H), 6.88-6.82 (m, 1H),3.75-3.53 (m, 4H), 2.15- 1.99 (m, 4H), 1.46-1.40 (m, 2H), 1.17-1.10 (m,2H). MF-DH- 431

 4.9%/95.80% 484.19 for C25H26F2N4O4/ 455.2 (M + 1) δ 12.12-11.99 (m,1H), 8.46- 8.44 (m, 1H), 8.24-8.22 (m, 1H), 8.15-8.12 (m, 1H), 8.06-8.02(m, 2H), 7.98-7.91 (m, 3H), 6.85 (d, J = 3.7 Hz, 1H), 3.77-3.54 (m, 4H),2.84-2.80 (m, 2H), 2.15- 2.03 (m, 4H), 1.49-1.45 (m, 6H). MF-DH- 432

 6.8%/99.48% 482.18 for C25H24F2N4O4/ 483.2 (M + 1) δ = 8.45 (d, J = 2.0Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 3.8 Hz, 1H), 8.05 (d, J= 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 3.5 Hz, 1H), 4.50-4.42 (m, 1H), 3.75-3.57 (m, 6H), 2.36-2.26 (m, 1H), 2.15-2.00 (m, 4H),1.97-1.80 (m, 3H). MF-DH- 433

 78.1%/99.82% 349.14 for C20H19N3O3/ 350.1 (M + 1) δ 13.08-12.95 (m,1H), 8.38 (d, J = 2.0 Hz, 1H), 8.18-8.09 (m, 6H), 6.86 (d, J = 3.8 Hz,1H), 3.76-3.40 (m, 4H), 1.69-1.50 (m, 6H) MF-DH- 434

 53.2%/94.01% 386.12 for C19H16F2N4O3/ 387.1 (M + 1) δ 13.73-12.61 (m,1H), 9.36- 9.34 (m, 1H), 8.66 (dd, J = 8.5, 2.5 Hz, 1H), 8.49 (d, J =1.9 Hz, 1H), 8.30-8.22 (m, 3H), 6.93 (d, J = 3.8 Hz, 1H), 3.76-3.50 (m,4H), 2.15-2.01 (m, 4H). MF-DH- 437

 61.3%/94.05% 455.21 for C24H27F2N5O2/ 456.2 (M + 1) δ 9.28-9.25 (m,1H), 8.63-8.59 (m, 1H), 8.48-8.46 (m, 1H), 8.37- 8.31 (m, 1H), 8.28-8.20(m, 3H), 6.93-6.89 (m, 1H), 3.87- 3.78 (m, 1H), 3.75-3.48 (m, 4H),2.16-2.02 (m, 4H), 1.65-1.55 (m, 4H), 0.87 (t, J = 7.4 Hz, 6H). MF-DH-438

 42.7%/95.24% 455.21 for C24H27F2N5O2/ 456.2 (M + 1) δ 9.31-9.27 (m,1H), 8.66-8.55 (m, 2H), 8.47 (d, J = 1.9 Hz, 1H), 8.28-8.21 (m, 3H),6.93-6.91 (m, 1H), 3.81-3.44 (m, 4H), 3.19 (d, J = 6.6 Hz, 2H),2.15-2.01 (m, 4H), 0.93 (s, 9H). MF-DH- 439

 41.6%/95.51% 366.13 for C20H16F2N4O/ 367.1 (M + 1) δ 8.48-8.46 (m, 1H),8.32-8.27 (m, 2H), 8.26-8.21 (m, 2H), 8.07- 8.03 (m, 2H), 6.91-6.88 (m,1H), 3.77-3.48 (m, 4H), 2.15- 2.02 (m, 4H). MF-DH- 440

 37.5%/98.38% 367.12 for C19H15F2N5O/ 368.1 (M + 1) δ 9.17 (d, J = 8.8Hz, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.57-8.50 (m, 3H), 8.28 (d, J = 2.0Hz, 1H), 6.94 (d, J = 3.9 Hz, 1H), 3.81- 3.38 (m, 4H), 2.15-2.02 (m, 4HMF-DH- 441

 32.4%/96.34% 382.12 for C20H16F2N4O2/ 383.1 (M + 1) δ 9.44-9.41 (m,1H), 9.27-9.23 (m, 1H), 9.15-9.10 (m, 1H), 8.58- 8.55 (m, 1H), 8.35-8.32(m, 2H), 7.01-6.98 (m, 1H), 3.79- 3.67 (m, 4H), 2.22-2.12 (m, 4H).MF-DH- 442

 28.7%/97.51% 367.12 for C19H15F2N5O/ 368.2 (M + 1) δ 9.17 (s, 1H), 8.58(d, J = 1.7 Hz, 1H), 8.38-8.36 (m, 1H), 8.36- 8.28 (m, J = 8.8 Hz, 2H),8.13 (d, J = 8.7 Hz, 2H), 3.84-3.44 (m, 4H), 2.16-2.01 (m, 4H). MF-DH-443

 31.2%/98.35% 337.07 for C17H12ClN5O/ 338.1 (M + 1) δ 9.18 (s, 1H), 8.75(d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H),8.13 (d, J = 8.7 Hz, 2H), 4.89 (br s, 2H), 4.73-4.51 (m, 2H), 4.16 (brs, 1H). MF-DH- 444

 7.2%/99.93% 452.2 for C21H19F2N3O2/ 453.2 (M + 1) δ 8.24-8.20 (m, 1H),8.11-8.04 (m, 3H), 7.75 (d, J = 8.5 Hz, 2H), 6.60-6.56 (m, 1H),4.24-4.21 (m, 1H), 3.73-3.52 (m, 4H), 2.79- 2.71 (m, 2H), 2.13-2.00 (m,4H), 1.68-1.58 (m, 2H), 1.04- 1.01 (m, 6H). MF-DH- 446

 3.5%/91.47% 437.17 for C23H21F2N5O2/ 438.2 (M + 1) δ 8.24-8.22 (m, 1H),8.11-8.07 (m, 3H), 7.78-7.73 (m, 2H), 7.39- 7.35 (m, 1H), 6.85-6.81 (m,1H), 6.58-6.56 (m, 1H), 3.73- 3.54 (m, 4H), 2.92-2.89 (m, 2H), 2.69-2.66(m, 2H), 2.11-2.00 (m, 4H). MF-DH- 448

 35.1%/97.53% 441.20 for C23H25F2N5O2/ 442.2 (M + 1) δ 9.30-9.27 (m,1H), 8.96-8.92 (m, 1H), 8.65 (s, 1H), 8.50-8.44 (m, 1H), 8.28-8.20 (m,2H), 8.15- 8.10 (m, 1H), 6.92-6.87 (m, 1H), 3.77-3.58 (m, 4H), 2.16-2.02 (m, 4H), 1.45-1.40 (s, 9H). MF-DH- 449

 12.8%/94.14% 382.11 for C20H16F2N4S/ 383.1 (M + 1) δ 8.41-8.38 (m, 1H),8.31-8.26 (m, 2H), 8.22-8.19 (m, 1H), 8.16- 8.13 (m, 1H), 8.08-8.02 (m,2H), 6.89-6.86 (m, 1H), 4.49- 4.43 (m, 2H), 3.76-3.70 (m, 2H), 2.31-2.21(m, 2H), 2.18-2.08 (m, 2H). MF-DH- 450

 31.3%/92.56% 481.19 for C25H25F2N5O3/ 482.0 (M + 1) δ 8.46-8.43 (m,1H), 8.25-8.21 (m, 1H), 8.16-8.10 (m, 1H), 8.06- 7.99 (m, 2H), 7.81-7.74(m, 2H), 7.59-7.40 (m, 1H), 7.00- 6.94 (m, 1H), 6.87-6.82 (m, 1H),4.43-4.27 (m, 1H), 3.75-3.45 (m, 6H), 2.25-2.03 (m, 5H), 1.97- 1.77 (m,3H). MF-DH- 451

32.78%/95.52% 472.19 for C24H26F2N4O4/ 473.0 (M + 1) δ 8.48-8.42 (m,1H), 8.27-8.20 (m, 1H), 8.13-8.09 (m, 1H), 8.01- 7.96 (m, 2H), 7.62-7.58(m, 2H), 6.86-6.82 (m, 1H), 3.60- 3.36 (m, 14H), 2.15-2.01 (m, 4H).MF-DH- 452

 45.3%/94.26% 410.14 for C19H16F2N8O/ 411.1 (M + 1) δ 9.41-8.99 (m, 1H),8.62-8.57 (m, 1H), 8.41-8.32 (m, 2H), 8.27- 8.24 (m, 1H), 8.18-8.12 (m,1H), 6.94-6.88 (m, 1H), 3.81- 3.50 (m, 4H), 2.13-2.03 (m, 4H). MF-DH-453

 32.6%/98.39% 410.14 for C19H16F2N8O/ 409.2 (M − 1) δ 9.44-9.41 (m, 1H),9.25 (d, J = 1.3 Hz, 1H), 9.14-9.12 (m, 1H), 8.58-8.55 (m, 1H),8.36-8.32 (m, 2H), 7.01-6.98 (m, 1H), 3.80- 3.68 (m, 4H), 2.21-2.12 (m,4H). MF-DH- 454

 13.3%/94.20% 426.13 for C20H16F2N6O3/ 425.2 (M − 1) δ 9.33-9.29 (m,1H), 8.96-8.92 (m, 1H), 8.82-8.78 (m, 1H), 8.50- 8.46 (m, 1H), 8.28-8.21(m, 2H), 6.92-6.89 (m, 1H), 3.75- 3.57 (m, 4H), 2.15-2.05 (m, 4H).MF-DH- 455

 5.8%/91.76% 409.15 for C20H17F2N7O/ 410.2 (M + 1) δ 9.32-9.28 (m, 1H),8.65-8.59 (m, 1H), 8.52-8.47 (m, 1H), 8.32- 8.25 (m, 4H), 6.95-6.90 (m,1H), 3.84-3.51 (m, 4H), 2.17- 2.06 (m, 4H). MF-DH- 456

 37.7%/92.01% 426.13 for C20H16F2N6O3/ 427.12 (M + 1) δ 13.29-13.14 (m,1H), 9.42 (d, J = 2.1 Hz, 1H), 8.78-8.71 (m, 1H), 8.49 (d, J = 1.7 Hz,1H), 8.33-8.24 (m, 2H), 8.24-8.17 (m, 1H), 6.94 (d, J = 3.7 Hz, 1H),3.82-3.55 (m, 4H), 2.08 (br d, J = 3.5 Hz, 4H). MF-DH- 457

 19.1%/97.36% 468.17 for C23H22F2N6O3/ 469.3 (M + 1) δ 8.97-8.92 (m,1H), 8.72-8.69 (m, 1H), 8.61-8.57 (m, 1H), 8.54- 8.47 (m, 2H), 8.29-8.24(m, 1H), 8.15-8.10 (m, 1H), 6.90- 6.86 (m, 1H), 3.79-3.54 (m, 4H),2.15-2.04 (m, 4H), 1.45 (s, 6H). MF-DH- 458

 23.8%/99.36% 452.14 for C22H18F2N6O3/ 453.2 (M + 1) δ 11.25-11.22 (m,1H), 8.98 (d, J = 2.2 Hz, 1H), 8.92-8.89 (m, 1H), 8.87-8.84 (m, 2H),8.47- 8.45 (m, 1H), 8.27-8.24 (m, 1H), 8.15-8.12 (m, 1H), 7.35-7.32 (m,1H), 6.90-6.87 (m, 1H), 3.74- 3.45 (m, 4H), 2.14-2.02 (m, 4H). MF-DH-459

 39.3%/99.82% 452.14 for C22H18F2N6O3/ 415.2 (M − 1) δ 12.42-12.37 (m,1H), 9.47 (d, J = 2.4 Hz, 1H), 9.14-9.12 (m, 1H), 8.93 (t, J = 2.1 Hz,1H), 8.56 (d, J = 1.8 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.29-8.24 (m,2H), 6.93 (d, J = 3.7 Hz, 1H), 6.50 (d, J = 1.8 Hz, 1H), 3.81-3.48 (m,4H), 2.12-2.02 (m, 4H). MF-DH- 460

 8.5%/95.03% 452.14 for C22H18F2N6O3/ 453.2 (M + 1) δ 12.23-12.19 (m,1H), 9.45- 9.42 (m, 1H), 8.77-8.72 (m, 1H), 8.55-8.53 (m, 1H), 8.51-8.49(m, 1H), 8.38-8.34 (m, 1H), 8.33- 8.31 (m, 1H), 8.29-8.27 (m, 1H),6.96-6.94 (m, 1H), 6.50- 6.47 (m, 1H), 3.79-3.56 (m, 4H), 2.16-2.04 (m,4H). MF-DH- 462

 38.5%/99.52% 348.14 for C20H17FN4O/ 349.1 (M + 1) δ 8.24-8.15 (m, 2H),8.10-8.06 (m, 2H), 7.93-7.88 (m, 2H), 7.49- 7.46 (m, 1H), 6.97-6.94 (m,1H), 5.03-4.85 (m, 1H), 3.79- 3.44 (m, 4H), 2.06-1.67 (m, 4H). MF-DH-463

 42.1%/99.89% 384.14 for C20H17FN4O/ 349.0 (M + 1) δ 8.98 (s, 1H),8.15-8.05 (m, 3H), 8.01-7.92 (m, 3H), 6.95 (d, J = 3.1 Hz, 1H),5.03-4.84 (m, 1H), 3.78-3.43 (m, 4H), 2.01- 1.66 (m, 4H). MF-DH- 464

 46.5%/99.47% 385.14 for C19H17F2N5O2/ 386.2 (M + 1) δ 9.10 (s, 1H),8.56 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.11 (s, 5H), 7.49(br s, 1H), 3.84- 3.42 (m, 4H), 2.16-2.03 (m, 4H). MF-DH- 465

 61.3%/99.17% 486.15 for C24H24F2N4O3S/ 487.2 (M + 1) δ 8.98 (d, J = 8.6Hz, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.56-8.47 (m, 2H), 8.26 (d, J = 1.9Hz, 1H), 8.19 (s, 1H), 6.89 (d, J = 3.9 Hz, 1H), 3.87-3.61 (m, 4H),3.22- 3.19 (m, 3H), 2.15-2.02 (m, 4H), 1.69 (s, 6H). MF-DH- 467

 16.8%/99.17% 427.18 for C22H23F2N5O2/ 428.2 (M + 1) δ 8.56-8.50 (m,1H), 8.44 (d, J = 2.0 Hz, 1H), 8.31-8.23 (m, 2H), 8.14-8.07 (m, 2H),7.85 (br d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 3.7Hz, 1H), 3.86-3.44 (m, 6H), 2.73-2.67 (m, 2H), 2.13-2.05 (m, 4H). MF-DH-468

 53.2%/99.80% 428.17 for C22H22F2N4O3/ 429.2 (M + 1) d, J = 2.0 Hz, 1H),8.29 (t, J = 1.8 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.13-8.07 (m, 2H),7.86 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 3.8 Hz,1H), 3.65-3.59 (m, 3H), 3.59-3.51 (m, 4H), 3.39-3.41 (m, 2H), 2.14- 2.02(m, 4H). MF-DH- 469

 41.5%/96.50% 386.12 for C19H16F2N4O3/ 387.2 (M + 1) δ 13.62-13.07 (m,1H), 9.09- 9.00 (m, 2H), 8.58-8.50 (m, 3H), 8.29-8.25 (m, 1H), 6.91 (d,J = 4.0 Hz, 1H), 3.82-3.49 (m, 4H), 2.16-2.01 (m, 4H). MF-DH- 470

 24.3%/99.63% 424.41 for C21H18F2N6O2/ 425.2 (M + 1) δ 9.35 (d, J = 2.6Hz, 1H), 9.13 (d, J = 1.8 Hz, 1H), 9.05-9.02 (m, 1H), 8.49 (d, J = 1.9Hz, 1H), 8.32-8.26 (m, 2H), 6.91 (d, J = 3.8 Hz, 1H), 3.76-3.48 (m, 4H),2.74 (s, 3H), 2.14-2.01 (m, 4H). MF-DH- 471

 46.3%/99.45% 424.15 for C19H16F2N4O3/ 425.2 (M + 1) δ 9.39 (d, J = 2.4Hz, 1H), 8.70 (dd, J = 2.6, 8.6 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H),8.32-8.23 (m, 3H), 6.93 (d, J = 3.8 Hz, 1H), 3.65 (br d, J = 4.9 Hz,4H), 2.72 (s, 3H), 2.16-2.00 (m, 4H). MF-DH- 472

 52.8%/98.32% 428.1 for C21H19F2N5O3/ 427.15 (M − 1) δ 8.90 (d, J = 2.2Hz, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.61 (t, J = 2.3 Hz, 1H), 8.44 (d, J= 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 3.7 Hz, 1H), 6.88(d, J = 3.7 Hz, 1H), 4.54 (t, J = 7.9 Hz, 2H), 4.25-4.15 (m, 2H), 3.78-3.48 (m, 4H), 2.15-2.01 (m, 4H). MF-DH- 477

12.4%/99.8% 413.17 for C21H19F2N5O3/ 414.2 (M + 1) δ 9.01-8.95 (m, 2H),8.71-8.66 (m, 1H), 8.57-8.51 (m, 2H), 8.46- 8.42 (m, 1H), 8.28-8.25 (m,1H), 6.89 (d, J = 3.9 Hz, 1H), 3.78-3.50 (m, 4H), 3.38-3.33 (m, 2H),2.15-2.03 (m, 4H), 2.17 (t, J = 7.2 Hz, 3H). MF-DH- 478

 33.6%/99.73% 456.17 for C22H22F2N6O3/ 457.2 (M + 1) δ 8.85 (d, J = 9.0Hz, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.44 (d, J= 3.8 Hz, 1H), 8.31-8.21 (m, 2H), 8.21- 8.11 (m, 3H), 6.86 (d, J = 3.9Hz, 1H), 5.04-4.94 (m, 1H), 4.35- 4.28 (m, 1H), 3.97-3.93 (m, 1H),3.83-3.69 (m, 4H), 3.34-3.27 (m, 2H), 2.15-2.02 (m, 4H). MF-DH- 479

 25.6%/94.32% 456.17 for C22H22F2N6O3/ 457.2 (M + 1) δ 8.93-8.89 (m,1H), 8.77-8.73 (m, 1H), 8.68-8.65 (m, 1H), 8.45- 8.41 (m, 1H), 8.28-8.25(m, 1H), 8.14 (br d, J = 3.7 Hz, 4H), 6.90 (d, J = 3.8 Hz, 1H), 5.06-4.97 (m, 1H), 4.38-4.35 (m, 1H), 4.00-3.96 (m, 1H), 3.80-3.59 (m, 4H),3.34-3.28 (m, 2H), 2.14- 2.02 (m, 4H). MF-DH- 480

 48.3%/97.43% 505.16 for C21H19F2N5O3/ 506.2 (M + 1) δ 8.71-8.68 (m,1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.12-8.08 (m, 2H),7.81-7.76 (m, 1H), 8.74-7.68 (m, 1H), 7.19-7.13 (m, 1H), 6.85 (s, 1H),3.76-3.49 (m, 4H), 3.51-3.48 (m, 2H), 3.18-3.21 (m, 2H), 2.91 (s, 3H),2.18-2.01 (m, 4H). MF-DH- 481

 35.0%/98.45% 550.13 for C25H25ClF2N4O4S/ 551.2 (M + 1) δ 8.62 (br d, J= 7.6 Hz, 1H), 8.47 (s, 1H), 8.32 (s, 2H), 8.25 (s, 1H), 8.22-8.14 (m,1H), 7.91 (s, 1H), 6.87 (d, J = 3.5 Hz, 1H), 4.29- 4.19 (m, 1H),3.75-3.50 (m, 4H), 3.35 (brs, 1H), 3.30-3.26 (m, 1H), 3.19-3.11 (m, 2H),2.21- 2.03 (m, 8H). MF-DH- 482

 61.4%/99.74% 419.1 for C19H16ClF2N5O2/ 420.1 (M + 1) δ 9.36-9.21 (m,1H), 9.03 (s, 1H), 8.74 (br s, 1H), 8.58-8.46 (m, 2H), 8.32-8.20 (m,2H), 7.77 (br s, 1H), 3.86-3.44 (m, 4H), 2.09 (br s, 4H). MF-DH- 484

 34.7%/99.58% 461.13 for C21H21F2N5O3S/ 462.2 (M + 1) δ 10.31 (s, 1H),8.83 (s, 1H), 8.44 (br s, 2H), 8.33 (s, 1H), 8.25 (s, 1H), 8.14 (d, J =3.8 Hz, 1H), 6.88 (d, J = 3.7 Hz, 1H), 3.77- 3.46 (m, 4H), 2.88-2.78 (m,1H), 2.13-2.01 (m, 4H), 1.06-0.99 (m, 4H). MF-DH- 485

 64.6%/99.52% 429.16 for C21H19F2N5O3/ 430.2 (M + 1) δ 10.14-10.10 (m,1H), 8.70 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H),8.43 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 3.7 Hz,1H), 6.86 (d, J = 3.7 Hz, 1H), 4.18 (d, J = 7.1 Hz, 2H), 3.76-3.49 (m,4H), 2.15-2.02 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H). MF-DH- 486

 23.4%/99.55% 481.19 for C25H25F2N5O3/ 482.3 (M + 1) δ 8.44 (d, J = 1.8Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.15-7.97 (m, 3H), 7.68-7.54 (m, 2H),7.44- 7.31 (m, 1H), 6.99-6.96 (m, 1H), 6.85-6.81 (m, 1H), 4.42- 4.24 (m,1H), 3.74-3.46 (m, 6H), 2.24-2.02 (m, 5H), 1.93-1.76 (m, 3H). MF-DH- 487

 41.8%/99.22% 427.18 for C22H23F2N5O2/ 428.2 (M + 1) δ 9.04-8.99 (m,1H), 8.58-8.53 (m, 1H), 8.47-8.40 (m, 1H), 8.27- 8.20 (m, 2H), 8.16-8.12(m, 1H), 7.17-7.03 (m, 2H), 6.89- 6.85 (m, 1H), 3.79-3.54 (m, 4H),2.13-2.04 (m, 4H), 1.58-1.55 (m, 6H). MF-DH- 489

 17.5%/96.47% 482.18 for C25H24F2N4O4/ 483.2 (M + 1) δ 12.77-12.14 (m,1H), 8.44 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.14-8.06 (m,2H), 7.99 (br d, J = 8.3 Hz, 1H), 7.69-7.62 (m, 1H), 7.54-7.48 (m, 1H),6.83 (d, J = 3.7 Hz, 1H), 4.47-4.40 (m, 1H), 3.77-3.51 (m, 6H), 2.14-2.01 (m, 4H), 1.98-1.83 (m, 3H). MF-DH- 495

 8.1%/95.00% 420.11 for C18H18F2N4O2/ 421.1 (M + 1) δ 8.46-8.41 (m, 2H),8.25 (d, J = 2.1 Hz, 1H), 8.14-8.08 (m, 2H), 7.84-7.75 (m, 2H), 7.50 (s,2H), 6.87 (d, J = 3.6 Hz, 1H), 3.77- 3.53 (m, 4H), 2.15-1.99 (m, 4H).MF-DH- 496

 12.2%/99.75% 420.11 for C18H18F2N4O2/ 421.1 (M + 1) δ 8.46 (d, J = 2.0Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.21-8.15 (m, 3H), 7.99 (d, J = 8.8Hz, 2H), 7.44 (s, 2H), 6.88 (d, J = 3.7 Hz, 1H), 3.76-3.49 (m, 4H),2.15- 2.02 (m, 4H). MF-DH- 497

 21.0%/99.02% 488.13 for C23H22F2N4O4S/ 489.1 (M + 1) δ 8.46 (d, J = 2.0Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.16 (br d, J = 3.7 Hz, 3H),7.74-7.68 (m, 1H), 7.58-7.53 (m, 1H), 6.86 (d, J = 3.7 Hz, 1H), 4.77 (s,2H), 4.16- 4.09 (m, 2H), 3.77-3.57 (m, 4H), 3.52 (t, J = 7.2 Hz, 2H),2.14- 2.04 (m, 4H). MF-DH- 498

 44.0%/99.46% 490.19 for C26H24F2N6O2/ 491.2 (M + 1) δ 8.49-8.42 (m,2H), 8.24 (d, J = 2.1 Hz, 1H), 8.11 (br d, J = 3.4 Hz, 2H), 7.96-7.91(m, 1H), 7.72- 7.67 (m, 1H), 6.85 (d, J = 3.7 Hz, 1H), 6.70 (s, 2H),3.74-3.49 (m, 4H), 2.14-2.01 (m, 4H), 1.77- 1.69 (m, 1H), 0.88-0.81 (m,2H), 0.68-0.62 (m, 2H). MF-DH- 499

 53.7%/99.19% 490.19 for C26H24F2N6O2/ 491.2 (M + 1) δ 11.07-10.99 (m,1H), 8.48- 8.41 (m, 2H), 8.28-8.16 (m, 3H), 8.00-7.94 (m, 1H), 7.74-7.65(m, 2H), 6.89-6.83 (m, 1H), 6.67- 6.58 (m, 1H), 3.77-3.59 (m, 5H),2.16-2.04 (m, 4H), 1.07- 1.00 (m, 2H), 0.97-0.92 (m, 2H). MF-DH- 500

 46.0%/99.61% 491.19 for C25H23F2N7O2/ 492.2 (M + 1) δ 11.26 (s, 1H),9.41 (d, J = 2.3 Hz, 1H), 9.09 (d, J = 1.6 Hz, 1H), 8.90-8.86 (m, 1H),8.49 (d, J = 1.8 Hz, 1H), 8.29-8.24 (m, 2H), 7.75 (d, J = 2.2 Hz, 1H),6.92 (d, J = 3.7 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 3.68 (br dd, J =7.3, 3.5 Hz, 5H), 2.08 (br s, 4H), 1.03 (br d, J = 3.8 Hz, 2H),0.99-0.93 (m, 2H). MF-DH- 501

 23.9%/92.56% 491.19 for C24H29F2N5O3/ 492.2 (M + 1) δ 9.32 (d, J = 2.6Hz, 1H), 9.06 (d, J = 1.7 Hz, 1H), 8.94 (t, J = 2.1 Hz, 1H), 8.47 (d, J= 1.8 Hz, 1H), 8.29-8.25 (m, 1H), 8.24- 8.20 (m, 1H), 6.91 (d, J = 3.7Hz, 1H), 6.76 (s, 2H), 5.18 (s, 1H), 3.81-3.49 (m, 4H), 2.13-2.03 (m,4H), 1.80-1.71 (m, 1H), 0.88- 0.83 (m, 2H), 0.70-0.66 (m, 2H). MF-DH-502

 3.5%/96.91% 483.12 for C19H15F2N5O2/ 383.95 (M + 1) δ 13.13-12.91 (m,1H), 8.64 (s, 1H), 8.41 (d, J = 1.6 Hz, 2H), 8.21 (d, J = 1.7 Hz, 1H),7.93 (br s, 1H), 6.77 (d, J = 3.5 Hz, 1H), 3.84-3.51 (m, 4H), 2.12-2.00(m, 4H). MF-DH- 507

 62.5%/97.07% 385.12 for C20H17F2N3O3/ 386.1 (M + 1) δ 13.39-12.96 (m,1H), 8.50- 8.48 (m, 1H), 8.48-8.43 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H),8.14- 8.12 (m, 1H), 7.97-7.91 (m, 1H), 7.70 (t, J = 7.9 Hz, 1H), 6.84(d, J = 3.7 Hz, 1H), 3.76-3.51 (m, 4H), 2.13-2.02 (m, 4H). MF-DH- 508

 21.8%/99.24% 536.11 for C24H23ClF2N4O4S/ 537.2 (M + 1) δ 8.48 (d, J =2.0 Hz, 1H), 8.24 (d, J = 1.9 Hz, 2H), 8.19-8.10 (m, 2H), 7.60-7.56 (m,1H), 6.87 (d, J = 3.8 Hz, 1H), 4.11-3.94 (m, 2H), 3.86-3.46 (m, 6H),3.39- 3.31 (m, 4H), 2.14-2.02 (m, 4H). MF-DH- 509

 44.5%/98.82% 409.17 for C22H21F2N5O/ 409.95 (M + 1) δ 9.20 (d, J = 2.2Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.48-8.44 (m, 2H), 8.27-8.24 (m, 1H),8.22- 8.19 (m, 1H), 6.89 (d, J = 3.7 Hz, 1H), 3.79-3.49 (m, 4H), 2.15-2.02 (m, 4H), 1.82 (s, 6H). MF-DH- 514

 23.5%/99.40% 409.15 for C20H17F2N7O/ 410.1 (M + 1) δ 8.47 (d, J = 2.0Hz, 1H), 8.28- 8.19 (m, 5H), 6.88 (d, J = 3.8 Hz, 1H), 3.79-3.53 (m,4H), 2.15- 2.02 (m, 4H). MF-DH- 515

 3.5%/99.37% 409.15 for C20H17F2N7O/ 410.1 (M + 1) δ 8.51 (t, J = 1.6Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.10 (d, J= 3.6 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.92- 7.85 (m, 1H), 7.67 (t, J= 7.9 Hz, 1H), 7.15-7.00 (m, 1H), 6.85 (d, J = 3.6 Hz, 1H), 3.74-3.57(m, 4H), 2.14-2.02 (m, 4H). MF-DH- 516

 8.1%/91.09% 409.15 for C20H17F2N7O/ 410.1 (M + 1) δ 9.19-9.13 (m, 2H),8.99-8.95 (m, 1H), 8.64-8.60 (m, 1H), 8.50- 8.46 (m, 1H), 8.27-8.24 (m,2H), 6.91-6.88 (m, 1H), 5.77- 5.74 (m, 1H), 3.70-3.59 (m, 4H), 2.13-2.05(m, 4H). MF-DH- 521

 4.8%/98.07% 490.16 for C20H17F2N7O/ 491.1 (M + 1) δ 8.57-8.51 (m, 1H),8.48 (d, J = 2.0 Hz, 1H), 8.33 (br d, J = 5.9 Hz, 2H), 8.20 (d, J = 3.8Hz, 1H), 7.92-7.89 (m, 1H), 7.73-7.67 (m, 1H), 6.89-6.86 (m, 1H), 4.54(s, 1H), 3.76-3.54 (m, 4H), 3.29- 3.25 (m, 2H), 2.16-2.03 (m, 4H),1.15-1.11 (m, 6H). MF-DH- 527

 11.0%/99.12% 472.14 for C23H22F2N4O3S/ 491.1 (M + 1) δ 8.47 (d, J = 2.0Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.19-8.12 (m, 2H), 8.10-8.05 (m, 1H),7.72- 7.67 (m, 1H), 7.59-7.51 (m, 1H), 6.86 (d, J = 3.7 Hz, 1H),4.93-4.64 (m, 1H), 4.60-4.54 (m, 1H), 4.48-3.93 (m, 4H), 3.89- 3.76 (m,4H), 2.16-2.02 (m, 4H). MF-DH- 124

 8.5%/99.91% 359.09 for C17H15ClFN5O/ 360.0 (M + 1) δ 10.02 (d, J = 0.9Hz, 1H), 8.67- 8.64 (m, 2H), 8.62-8.60 (m, 1H), 8.59-8.57 (m, 1H), 8.20(d, J = 2.0 Hz, 1H), 5.04-4.85 (m, 1H), 3.84-3.44 (m, 4H), 2.06-1.74 (m,4H). MF-DH- 166

 49.1%/95.19% 373.11 for C18H17ClFN5O/ 374.0 (M + 1) δ 9.80 (s, 1H),8.60 (d, J = 1.8 Hz, 1H), 8.57-8.51 (m, 2H), 8.19 (d, J = 2.0 Hz, 1H),5.05-4.84 (m, 1H), 3.82-3.38 (m, 4H), 2.58 (s, 3H), 2.04-1.71 (m, 4H).MF-DH- 169

 51.1%/99.91% 373.11 for C18H17ClFN5O/ 374.0 (M + 1) δ 9.26 (s, 2H),8.51-8.49 (m, 1H), 8.46 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 5.02-4.84 (m,1H), 3.80- 3.41 (m, 4H), 2.71 (s, 3H), 2.04- 1.72 (m, 4H). MF-DH- 175

15.1%/99.0% 367.13 for C20H18FN3O3/ 368.1 (M + 1) δ 8.37-8.35 (m, 1H),8.15 (s, 1H), 7.93 (d, J = 3.3 Hz, 1H), 7.46 (s, 1H), 7.28 (br d, J =8.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 3.3 Hz, 1H), 6.12(s, 2H), 5.00-4.86 (m, 1H), 3.78- 3.38 (m, 4H), 2.00-1.72 (m, 4H).MF-DH- 178

 16.1%/95.85% 338.15 for C19H19FN4O/ 339.1 (M + 1) δ 9.18 (s, 1H), 9.14(s, 2H), 7.71- 7.63 (m, 3H), 7.30-7.26 (m, 1H), 5.01-4.81 (m, 1H),3.71-3.35 (m, 4H), 2.33 (d, J = 0.98 Hz, 3H), 1.99-1.81 (m, 2H),1.79-1.65 (m, 2H). MF-DH- 180

 9.1%/99.31% 338.15 for C19H19FN4O/ 339.1 (M + 1) δ 9.14 (d, J = 1.22Hz, 1H), 8.59 (dd, J = 2.51, 1.53 Hz, 1H), 8.52- 8.47 (m, 2H), 8.10-8.07(m, 1H), 7.68 (d, J = 1.10 Hz, 1H), 7.36 (dd, J = 8.62, 1.53 Hz, 1H),5.02, 4.83 (m, 1H), 3.76, 3.38 (m, 4H), 2.35 (d, J = 0.73 Hz, 3H),2.01-1.66 (m, 4H). MF-DH- 181

 6.1%/99.94% 367.17 for C21H22FN3O2/ 368.2 (M + 1) δ 8.48 (d, J = 1.8Hz, 1H), 8.19- 8.10 (m, 3H), 8.03 (d, J = 1.7 Hz, 1H), 7.00 (d, J = 8.8Hz, 2H), 5.03-4.84 (m, 1H), 3.89 (s, 3H), 3.80-3.76 (m, 3H), 3.72-3.43(m, 4H), 2.03-1.71 (m, 4H). MF-DH- 186

 10.6%/99.77% 411.20 for C23H26FN3O3/ 412.1 (M + 1) δ 7.81 (s, 1H), 7.54(d, J = 8.8 Hz, 2H), 7.51-7.33 (m, 1H), 7.23 (dd, J = 8.7, 2.8 Hz, 3H),5.01- 4.85 (m, 1H), 3.88 (s, 3H), 3.73- 3.67 (m, 2H), 3.67-3.31 (m, 4H),3.20 (s, 3H), 3.17-3.02 (m, 2H), 2.00-1.66 (m, 4H). MF-DH- 187

 61.9%/99.32% 367.17 for C21H22FN3O2/ 368.1 (M + 1) δ 7.81 (s, 1H), 7.54(d, J = 8.8 Hz, 2H), 7.41-7.19 (m, 4H), 5.00- 4.85 (m, 1H), 3.88 (s,3H), 3.75- 3.58 (m, 4H), 3.20 (s, 3H), 1.99- 1.68 (m, 4H). MF-DH- 189

 12.6%/99.27% 352.16 for C21H21FN2O2/ 353.1 (M + 1) δ 7.73 (s, 1H), 7.65(d, J = 3.2 Hz, 1H), 7.55-7.43 (m, 3H), 7.28- 7.18 (m, 1H), 7.14 (d, J =8.9 Hz, 2H), 6.73 (d, J = 3.2 Hz, 1H), 5.00-4.83 (m, 1H), 3.84 (s, 3H),3.70-3.36 (m, 4H), 1.99-1.65 (m, 4H). MF-DH- 190

 28.2%/99.47% 366.17 for C22H23FN2O2/ 367.2 (M + 1) δ 7.66 (s, 1H),7.49-7.41 (m, 4H), 7.22 (br d, J = 8.4 Hz, 1H), 7.12 (br d, J = 8.9 Hz,2H), 5.01- 4.83 (m, 1H), 3.83 (s, 3H), 3.70- 3.46 (m, 4H), 2.33 (s, 3H),1.99- 1.69 (m, 4H). MF-DH- 193

 35.1%/95.66% 381.19 for C22H24FN3O2/ 382.1 (M + 1) δ 7.68 (s, 1H), 7.47(d, J = 8.80 Hz, 2H), 7.23 (dd, J = 8.9, 1.10 Hz, 1H), 7.21-7.14 (m,2H), 7.14-7.04 (m, 1H), 5.01-4.82 (m, 1H), 3.86 (s, 3H), 3.70-3.36 (m,4H), 2.72 (q, J = 7.54 Hz, 2H), 2.01-1.82 (m, 2H), 1.73 (br s, 2H), 1.24(t, J = 7.46 Hz, 3H). MF-DH- 199

 17.1%/91.40% 367.17 for C21H22FN3O2/ 368.1 (M + 1) δ 8.51 (d, J = 1.34Hz, 1H), 8.31 (s, 1H), 8.05 (d, J = 1.47 Hz, 1H), 7.87-7.78 (m, 2H),7.32 (t, J = 7.95 Hz, 1H), 6.79 (dd, J = 8.13, 2.14 Hz, 1H), 5.04-4.85(m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.75-3.44 (m, 4H), 2.03-1.70 (m,4H). MF-DH- 200

 27.1%/99.91% 367.17 for C21H22FN3O2/ 368.1 (M + 1) δ 8.57 (s, 1H),8.52-8.40 (m, 1H), 8.37 (s, 1H), 8.34-8.25 (m, 1H), 7.28 (br d, J = 7.34Hz, 1H), 7.13 (d, J = 8.19 Hz, 1H), 7.06 (t, J = 7.40 Hz, 1H), 5.04-4.87(m, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.79-3.51 (m, 4H), 2.04-1.72 (m,4H). MF-DH- 204

 17.1%/97.52% 353.15 for C20H20FN3O2/ 354.1 (M + 1) δ 11.89 (br s, 1H),8.51 (d, J = 1.47 Hz, 1H), 8.23 (d, J = 2.69 Hz, 1H), 8.09 (br d, J =8.68 Hz, 2H), 8.06- 7.96 (m, 1H), 7.01 (d, J = 8.80 Hz, 2H), 4.99-4.88(m, 1H), 3.79 (s, 3H), 3.73-3.51 (m, 4H), 2.02-1.87 (m, 2H), 1.77 (br d,J = 2.08 Hz, 2H). MF-DH- 206

 16.1%/99.65% 349.18 for C21H23N3O2/ 350.2 (M + 1) δ 7.59 (s, 1H),7.54-7.42 (m, 2H), 7.21-7.15 (m, 3H), 7.12-7.06 (m, 1H), 3.86 (s, 3H),3.72-3.32 (m, 4H), 2.41 (s, 3H), 1.70-1.42 (m, 6H). MF-DH- 237

 3.3%/99.58% 299.20 for C18H25N3O/ 300.3 (M + 1) δ 9.29 (s, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.47 (dd, J = 8.4, 1.2 Hz, 1H), 4.55(br t, J = 7.2 Hz, 1H), 3.70-3.21 (m, 4H), 2.04-1.95 (m, 4H), 1.66-1.37(m, 6H), 0.79-0.70 (m, 6H). MF-DH- 242

 52.1%/99.77% 354.15 for C18H19FN4O2/ 355.1 (M + 1) δ 8.23 (s, 1H), 7.87(d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.66 (dd, J = 8.6, 1.2Hz, 1H), 7.24 (d, J = 8.9 Hz, 2H), 5.03- 4.85 (m, 1H), 3.88 (s, 3H),3.80- 3.35 (m, 4H), 2.02-1.68 (m, 4H). MF-DH- 243

 24.1%/99.17% 336.16 for C19H21FN4O/ 337.2 (M + 1) δ 8.17 (s, 1H), 7.86(d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.62 (dd, J = 8.6, 1.2Hz, 1H), 7.24 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H), 3.75-3.34 (m, 4H),1.70- 1.44 (m, 6H). MF-DH- 245

 48.2%/98.74% 335.16 for C20H21N3O2/ 336.2 (M + 1) δ 8.39 (s, 1H), 7.91(s, 1H), 7.75- 7.63 (m, 3H), 7.46 (dd, J = 8.7, 1.3 Hz, 1H), 7.15 (d, J= 8.9 Hz, 2H), 3.85 (s, 3H), 3.66-3.34 (m, 4H), 1.67-1.48 (m, 6H).MF-DH- 246

 38.8%/97.11% 387.11 for C20H19ClFN3O2/ 388.1 (M + 1) δ 7.84 (s, 1H),7.76 (d, J = 8.8 Hz, 1H), 7.68-7.63 (m, 2H), 7.63- 7.57 (m, 1H), 7.16(br d, J = 8.9 Hz, 2H), 5.03-4.84 (m, 1H), 3.85 (s, 3H), 3.72-3.34 (m,4H), 2.02- 1.66 (m, 4H). MF-DH- 247

 58.4%/95.80% 369.12 for C20H20ClN3O2/ 370.1 (M + 1) δ 781-7.79 (m, 2H),7.71-7.62 (m, 2H), 7.58-7.53 (m, 1H), 7.18- 7.12 (m, 2H), 3.82 (s, 3H),3.73- 3.34 (m, 4H), 1.71-1.42 (m, 6H). MF-DH- 249

 10.1%/98.21% 385.12 for C20H17F2N3O3/ 386.2 (M + 1) δ 8.35 (s, 1H),8.13 (s, 1H), 8.05- 7.98 (m, 2H), 7.78-7.67 (m, 1H), 7.62-7.58 (m, 1H),6.81 (s, 1H), 3.70-3.35 (m, 4H), 1.68- 1.48 (m, 6H). MF-DH- 271

 26.7%/95.09% 374.07 for C18H16Cl2N4O/ 375.0 (M + 1) δ 9.03 (d, J = 1.8Hz, 1H), 8.75- 8.71 (m, 1H), 8.42 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H),7.83 (s, 1H), 7.64 (br d, J = 8.7 Hz, 1H), 3.71- 3.34 (m, 4H), 1.68-1.49(m, 6H). MF-DH- 272

 51.1%/98.82% 369.12 for C20H20ClN3O2/ 370.2 (M + 1) δ 7.92 (d, J = 8.8Hz, 1H), 7.79 (s, 1H), 7.62-7.49 (m, 2H), 7.36- 7.26 (m, 2H), 7.04 (dd,J = 8.3, 2.3 Hz, 1H), 3.86 (s, 3H), 3.74- 3.33 (m, 4H), 1.69-1.45 (m,6H). MF-DH- 284

 6.6%/97.83% 347.18 for C19H23F2N3O/ 348.2 (M + 1) δ 8.29-8.27 (m, 1H),8.00 (d, J = 1.9 Hz, 1H), 7.78-7.76 (m, 1H), 6.57-6.55 (m, 1H),4.99-4.89 (m, 1H), 3.65-3.42 (m, 4H), 2.16 (br d, J = 19.6 Hz, 6H),2.06- 1.99 (m, 2H), 1.64-1.51 (m, 6H). MF-DH- 287

 60.4%/99.06% 349.18 for C21H23N3O2/ 350.2 (M + 1) δ 8.07 (s, 1H), 7.87(d, J = 3.7 Hz, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H),6.81 (d, J = 3.7 Hz, 1H), 3.82 (s, 3H), 3.75- 3.59 (m, 2H), 3.16 (br s,2H), 2.47 (s, 3H), 1.60 (br s, 4H), 1.53- 1.32 (m, 2H). MF-DH- 288

 15.1%/96.48% 351.16 for C20H21N3O3/ 352.2 (M + 1) δ 11.16-10.98 (m,1H), 7.98- 7.92 (m, 1H), 7.73-7.63 (m, 3H), 7.11-7.05 (m, 2H), 6.91-6.86(m, 1H), 3.83 (s, 3H), 3.43 (br s, 4H), 1.64-1.51 (m, 6H). MF-DH- 289

 37.1%/99.94% 360.16 for C21H20N4O2/ 361.1 (M + 1) δ 8.46 (s, 1H), 8.25(d, J = 3.7 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H),6.94 (d, J = 3.7 Hz, 1H), 3.84 (s, 3H), 3.82- 3.58 (m, 2H), 3.29-3.22(m, 2H), 1.68-1.44 (m, 6H). MF-DH- 290

 39.9%/94.39% 350.17 for C20H22N4O2/ 351.2 (M + 1) δ 7.82-7.80 (m, 1H),7.69 (d, J = 8.9 Hz, 2H), 7.50-7.48 (m, 1H), 7.06 (d, J = 9.0 Hz, 2H),6.89- 6.86 (m, 1H), 6.47-6.43 (m, 2H), 3.81 (s, 3H), 3.51-3.44 (m, 4H),1.63-1.51 (m, 6H). MF-DH- 292

 19.3%/99.93% 340.11 for C18H17ClN4O/ 341.1 (M + 1) δ 9.06 (d, J = 2.1Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.41 (br d, J = 2.1 Hz,1H), 8.05- 7.94 (m, 2H), 7.55 (br d, J = 8.7 Hz, 1H), 3.70-3.55 (m, 4H),1.68- 1.48 (m, 6H). MF-DH- 330

 46.6%/99.04% 421.24 for C25H31N3O3/ 422.3 (M + 1) 1δ 8.12-8.08 (m, 1H),7.93 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.9 Hz,2H), 6.46 (s, 1H), 4.22 (s, 1H), 3.85 (s, 3H), 3.68-3.46 (m, 4H), 2.69-2.65 (m, 2H), 1.69-1.51 (m, 8H), 1.04 (s, 6H). MF-DH- 389

 3.5%/99.81% 331.14 for C19H17N5O/ 332.2 (M + 1) δ 9.44-9.36 (m, 1H),8.70 (dd, J = 8.5, 2.1 Hz, 1H), 8.32 (s, 1H), 8.24-8.12 (m, 2H),8.12-8.04 (m, 1H), 6.84 (d, J = 3.7 Hz, 1H), 3.59-3.25 (m, 4H),1.58-1.38 (m, 6H). MF-DH- 346

 34.2%/99.29% 366.19 for C21H23FN4O/ 367.1 (M + 1) δ 8.31 (s, 1H), 8.13(s, 1H), 7.87- 7.83 (m, 1H), 7.58-7.53 (m, 2H), 6.91-6.85 (m, 2H), 6.72(s, 1H), 5.03-4.82 (m, 1H), 3.78- 3.37 (m, 4H), 2.98 (s, 6H), 2.03- 1.65(m, 4H). MF-DH- 241

 24.2%/89.16% 335.16 for C20H21N3O2/ 336.2 (M + 1) δ 8.48-8.46 (m, 1H),7.78-7.76 (m, 1H), 7.66-7.56 (m, 3H), 7.14- 7.01 (m, 2H), 6.94-6.92 (m,1H), 3.84 (s, 3H), 3.68-3.35 (m, 4H), 1.67-1.42 (m, 6H). MF-DH- 424

 47.3%/94.90% 385.12 for C20H17F2N3O3/ 386.2 (M + 1) δ 13.42-12.82 (m,1H), 8.48- 8.46 (m, 1H), 8.26-8.20 (m, 1H), 8.18-8.06 (m, 5H), 6.86-6.84 (m, 1H), 3.80-3.52 (m, 4H), 2.18-2.01 (m, 4H). MF-DH- 425

 42.0%/98.59% 386.12 for C19H16F2N4O3/ 387.2 (M + 1) δ 13.82-13.42 (m,1H), 9.34- 9.32 (m, 1H), 9.04 (s, 1H), 8.88- 8.86 (m, 1H), 8.48 (s, 1H),8.28- 8.22 (m, 2H), 6.90-6.88 (m, 1H), 3.82-3.52 (m, 4H), 2.18- 2.01 (m,4H). MF-DH- 476

 34.0%/88.98% 449.17 for C24H21F2N5O2/ 450.2 (M + 1) δ 8.52 (d, J = 1.8Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.18-8.12 (m, 2H), 7.97 (d, J = 8.7Hz, 2H), 5.74 (s, 1H), 3.83-3.44 (m, 4H), 2.14-2.03 (m, 4H), 1.39 (s,6H). MF-DH- 517

 8.0%/96.91% 449.18 for C23H21F2N7O/ 450.1 (M + 1) δ 13.97-13.91 (m,1H), 9.13- 9.09 (m, 2H), 8.84-8.82 (m, 1H), 8.49-8.46 (m, 1H), 8.27-8.22(m, 2H), 6.91-6.87 (m, 1H), 3.78- 3.53 (m, 4H), 2.18-2.05 (m, 5H),1.13-0.98 (m, 4H). MF-DH- 518

 12.0%/96.52% 449.18 for C13H21F2N7O/ 450.1 (M + 1) δ 14.15 (s, 1H),9.41-9.13 (m, 1H), 8.66-8.41 (m, 2H), 8.31- 8.17 (m, 3H), 6.99-6.87 (m,1H), 3.78-3.54 (m, 4H), 2.18-2.02 (m, 5H), 1.05-0.79 (m, 4H). MF-DH- 519

 8.0%/91.47% 477.13 for C21H16F5N7O/ 478.1 (M + 1) δ 15.75-15.70 (m,1H), 9.40- 9.38 (m, 1H), 8.76-8.70 (m, 1H), 8.51-8.49 (m, 1H), 8.36-8.30(m, 2H), 8.29-8.27 (m, 1H), 6.96- 6.91 (m, 1H), 3.83-3.57 (m, 4H),2.16-2.05 (m, 4H). MF-DH- 520

13.4%/98.9% 518.22 for C28H28F2N6O2/ 519.2 (M + 1) δ 10.70-10.67 (m,1H), 9.41- 9.39 (m, 1H), 9.13-9.11 (m, 1H), 8.89-8.83 (m, 2H), 8.50-8.48(m, 1H), 8.29-8.26 (m, 2H), 8.15- 8.11 (m, 1H), 7.49-7.45 (m, 1H),6.94-6.92 (m, 1H), 3.78- 3.54 (m, 4H), 2.15-2.02 (m, 4H), 1.33-1.32 (m,9H). MF-DH- 538

 43.0%/94.34% 471.20 for C25H27F2N3O4/ 472.2 (M + 1) δ 12.46-12.12 (m,1H), 8.21 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.07 (d, J =2.0 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 6.56 (s, 1H), 4.22 (s, 1H),3.75-3.46 (m, 4H), 2.69-2.62 (m, 2H), 2.13- 1.99 (m, 4H), 1.67-1.60 (m,2H), 1.01 (s, 6H). MF-DH- 542

 35.0%/90.64% 509.22 for C17H29F2N5O3/ 510.2 (M + 1) δ 8.24-8.17 (m,3H), 8.07 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 6.57 (s, 1H),4.22 (s, 1H), 3.72-3.46 (m, 4H), 2.79-2.65 (m, 5H), 2.12-1.98 (m, 4H),1.68- 1.62 (m, 2H), 1.03-0.99 (m, 6H). MF-DH- 544

 13.0%/99.40% 477.20 for C26H25F2N5O2/ 478.2 (M + 1) δ 8.22-8.20 (m,1H), 8.14-8.09 (m, 2H), 8.05-8.03 (m, 1H), 7.77- 7.72 (m, 2H), 3.81-3.52(m, 4H), 3.44-3.37 (m, 2H), 2.13- 2.05 (m, 4H), 1.59-1.54 (m, 2H), 1.34(s, 6H). MF-DH- 562

 49.3%/97.41% 363.16 for C21H21N3O3/ 364.2 (M + 1) δ 13.18-12.81 (m,1H), 8.38 (d, J = 2.0 Hz, 1H), 8.19-8.09 (m, 6H), 6.86 (d, J = 3.8 Hz,1H), 4.42-4.20 (m, 1H), 3.70-3.51 (m, 1H), 3.09-2.69 (m, 2H), 1.84- 1.76(m, 1H), 1.70-1.40 (m, 3H), 1.36-1.01 (m, 2H), 0.98- 0.64 (m, 3H).MF-DH- 574 (absolute stereo- chemistry not deter- mined)

 43.6%/99.22% 334.12 for C19H15FN4O/ 335.1 (M + 1) δ 8.58 (brs, 1H),8.38-8.25 (m, 3H), 8.25-8.18 (m, 1H), 8.05 (d, J = 8.8 Hz, 2H), 6.89 (d,J = 3.8 Hz, 1H), 5.50-5.23 (m, 1H), 4.06- 3.58 (m, 4H), 2.27-2.02 (m,2H). MF-DH- 575 (absolute stereo- chemistry not deter- mined)

 43.6%/98.76% 334.12 for C19H15FN4O/ 335.1 (M + 1) δ 8.58 (brs, 1H),8.37-8.28 (m, 3H), 8.28-8.16 (m, 1H), 8.05 (d, J = 8.9 Hz, 2H), 6.89 (d,J = 3.8 Hz, 1H), 5.49-5.23 (m, 1H), 4.04- 3.58 (m, 4H), 2.29-2.02 (m,2H).Methods of Use

In one aspect, provided herein are methods for treating variousdisorders in a subject in need thereof, comprising administering to saidsubject a compound described herein. In some embodiments, the inhibitorsof hydroxyprostaglandin dehydrogenase provided herein may be used forthe prevention or treatment of a disease or a disorder that isassociated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH)and/or decreased levels of prostaglandins. In some embodiments, theinhibitors of hydroxyprostaglandin dehydrogenase provided herein may beused for the prevention or treatment of a disease or a disorder in whichit is desirable to increase prostaglandin levels in the subject havingsaid disease or disorder.

In some embodiments, the methods for treating the disorders comprisesadministering to said subject a 15-PGDH inhibitor. In some embodiments,a compound described herein is the 15-PGDH inhibitor. In someembodiments, a compound having Formula I, Formula II, or Formula III isthe 15-PGDH inhibitor. In some embodiments, the methods compriseadministering a therapeutically effective amount of a compound describedherein. In some embodiments, the methods comprise administering atherapeutically effective amount of a compound having Formula I, FormulaII, or Formula III. In some embodiments, the compound described hereinis a 15-PGDH inhibitor. In some embodiments, the compound having FormulaI, Formula II, or Formula III is a 15-PGDH inhibitor. In someembodiments, the administration takes place in vitro. In otherembodiments, the administration takes place in vivo.

As used herein, a therapeutically effective amount of a 15-PGDHinhibitor refers to an amount sufficient to effect the intendedapplication, including but not limited to, disease treatment, as definedherein. Also contemplated in the subject methods is the use of asub-therapeutic amount of a 15-PGDH inhibitor for treating an intendeddisease condition.

The amount of the 15-PGDH inhibitor administered may vary depending uponthe intended application (in vitro or in vivo), or the subject anddisease condition being treated, e.g., the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

Measuring inhibition of biological effects of 15-PGDH can compriseperforming an assay on a biological sample, such as a sample from asubject. Any of a variety of samples may be selected, depending on theassay. Examples of samples include, but are not limited to, bloodsamples (e.g. blood plasma or serum), exhaled breath condensate samples,bronchoalveolar lavage fluid, sputum samples, urine samples, and tissuesamples.

A subject being treated with a 15-PGDH inhibitor may be monitored todetermine the effectiveness of treatment, and the treatment regimen maybe adjusted based on the subject's physiological response to treatment.For example, if inhibition of a biological effect of 15-PGDH is above orbelow a threshold, the dosing amount or frequency may be decreased orincreased, respectively. The methods can further comprise continuing thetherapy if the therapy is determined to be efficacious. The methods cancomprise maintaining, tapering, reducing, or stopping the administeredamount of a compound in the therapy if the therapy is determined to beefficacious. The methods can comprise increasing the administered amountof a compound in the therapy if it is determined not to be efficacious.Alternatively, the methods can comprise stopping therapy if it isdetermined not to be efficacious. In some embodiments, treatment with a15-PGDH inhibitor is discontinued if inhibition of the biological effectis above or below a threshold, such as in a lack of response or anadverse reaction. The biological effect may be a change in any of avariety of physiological indicators.

In general, a 15-PGDH inhibitor is a compound that inhibits one or morebiological effects of 15-PGDH. Such biological effects may be inhibitedby about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, or more.

In some other embodiments, the subject methods are useful for treating adisease condition associated with 15-PGDH. Any disease condition thatresults directly or indirectly from an abnormal activity or expressionlevel of 15-PGDH can be an intended disease condition.

In one aspect, provided herein is a method of promoting and/orstimulation skin pigmentation, comprising administering one or more ofthe compositions described herein to a subject in need thereof.Inhibitors of 15-PGDH are known to promote skin pigmentation (Markowitzet. al., WO 2015/065716). The hydroxyprostaglandin dehydrogenaseinhibitors described herein can be used for promoting and/or inducingand/or stimulating pigmentation of the skin and/or skin appendages,and/or as an agent for preventing and/or limiting depigmentation and/orwhitening of the skin and/or skin appendages, in particular as an agentfor preventing and/or limiting canities. In some embodiments, the15-PGDH inhibitors provided herein can be applied to skin of a subject,e.g., in a topical application, to promote and/or stimulate pigmentationof the skin and/or hair growth, inhibit hair loss, and/or treat skindamage or inflammation, such as skin damage caused by physical orchemical irritants and/or UV-exposure.

In another aspect, provided herein is a method of inhibiting hair loss,comprising administering one or more of the compositions describedherein to a subject in need thereof. It is known that prostaglandinsplay an important role in hair growth. Prostaglandins such asprostaglandin A1, F2a and E2 are stored in hair follicles or adjacentskin environments and have been shown to be essential in maintaining andincreasing hair density (Colombe L et. al, 2007, Exp. Dermatol, 16(9),762-9). It has been reported that 15-PGDH, which is involved in thedegradation of prostaglandins is present in the hair follicle dermalpapillae, inactivates prostaglandins, especially, PGF2a and PGE2, tocause scalp damage and alopecia (Michelet J F et. al., 2008, Exp.Dermatol, 17(10), 821-8). Thus, the hydroxyprostaglandin dehydrogenaseinhibitors described herein that have a suppressive or inhibitoryactivity against 15-PGDH can improve scalp damage, prevent alopecia andpromote hair growth and be used in a pharmaceutical composition for theprevention of alopecia and the promotion of hair growth.

In another aspect, provided herein is a method of preventing and/ortreating skin inflammation and/or damage, comprising administering oneor more of the compositions described herein to a subject in needthereof.

In another aspect, provided herein is a method of preventing and/ortreating vascular insufficiency, comprising administering one or more ofthe compositions described herein to a subject in need thereof.Prostaglandins including prostaglandin homologues produced in the bodyhave been known to maintain the proper action of the blood vessel wall,especially to contribute to vasodilation for blood flow, preventingplatelet aggregation and modulating the proliferation of smooth musclethat surrounds blood vessel walls (Yan. Cheng et. al., 2006, J. Clin.,Invest). In addition, the inhibition of prostaglandins production or theloss of their activity causes the degeneration of the endothelium in theblood vessel walls, platelet aggregation and the dysfunction of cellularmechanism in the smooth muscle. Among others, the production ofprostaglandins in blood vessels was shown to be decreased inhypertension patients, including pulmonary artery hypertension, the15-PGDH inhibitors described herein can be used in a pharmaceuticalcomposition for the prevention or the treatment of cardiovasculardisease and/or diseases of vascular insufficiency, such as Raynaud'sdisease, Buerger's disease, diabetic neuropathy, and pulmonary arteryhypertension.

In another aspect, provided herein is a method of preventing, treating,minimizing and/or reversing congestive heart failure, cardiomyopathy,comprising administering one or more of the compositions describedherein to a subject in need thereof. In another aspect, provided hereinis a method of reducing cardiac ejection fraction, comprisingadministering one or more of the compositions described herein to asubject in need thereof. It has been shown that administration of a15-PGDH inhibitor can be used to treat, prevent, minimize, and/orreverse congestive heart failure, cardiomyopathy, and/or reduction ofcardiac ejection fraction (Markowitz et. al., WO2018/187810). As such,the hydroxyprostaglandin dehydrogenase inhibitors described herein canbe administered to a subject in need to treat, prevent, minimize and/orreverse congestive heart failure, cardiomyopathy, and/or reduction ofcardiac ejection fraction.

In another aspect, provided herein is a method of preventing and/ortreating a gastrointestinal disease, comprising administering one ormore of the compositions described herein to a subject in need thereof.Prostaglandins are essential for maintaining the mechanism forprotecting and defending gastric mucus membrane (Wallace J L., 2008,Physiol Rev., 88(4), 1547-65, S. J. Konturek et al., 2005, Journal ofPhysiology and Pharmacology, 56(5)). The inhibitors ofhydroxyprostaglandin dehydrogenase described herein show a suppressiveor inhibitory activity against 15-PGDH, which degrades prostaglandinsthat protect gastric mucus membranes. As such, the hydroxyprostaglandindehydrogenase inhibitors can be effective for the prevention or thetreatment of gastrointestinal diseases, inter alia, gastritis andgastric ulcer. In addition, the hydroxyprostaglandin dehydrogenaseinhibitors provided herein may be used to prevent and/or treat otherforms of intestinal injury including toxicity from radiation and/orchemotherapy, and chemotherapy-induced mucositis.

Additionally, it has been shown that administration of 15-PGDHinhibitors, alone or in combination with corticosteroids and/or TNFinhibitors can treat intestinal, gastrointestinal, or bowel disorderssuch as oral ulcers, gum disease, gastritis, colitis, ulcerativecolitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease(Markowitz et. al., WO 2018/102552). As such, the hydroxyprostaglandindehydrogenase inhibitors provided herein can be used to treat and/orprevent treat intestinal, gastrointestinal, or bowel disorders such asoral ulcers, gum disease, gastritis, colitis, ulcerative colitis,gastric ulcers, inflammatory bowel disease, and Crohn's disease.

In another aspect, provided herein is a method of preventing and/ortreating renal dysfunction, comprising administering one or more of thecompositions described herein to a subject in need thereof. In thekidney, prostaglandins modulate renal blood flow and may serve toregulate urine formation by both renovascular and tubular effects. Inclinical studies, inhibitors of prostaglandin have been used to improvecreatinine clearance in patients with chronic renal disease, to preventgraft rejection and cyclosporine toxicity in renal transplant patients,to reduce the urinary albumin excretion rate andN-acetyl-beta-D-glucosaminidase levels in patients with diabeticnephropathy (Porter, Am., 1989, J. Cardiol., 64: 22E-26E). Furthermore,it has been reported that prostaglandins serve as vasodilators in thekidney, and, thus, the inhibition of prostaglandin production in thekidney results in renal dysfunction (Hao. C M, 2008, Annu Rev Physiol,70, 357.about.77). The hydroxyprostaglandin dehydrogenase inhibitorsdescribed herein have a suppressive or inhibitory activity against15-PGDH that degrades prostaglandins and can be used for the preventionand/or treatment of renal diseases that are associated with renaldysfunction.

In another aspect, provided herein is a method of stimulation boneresorption and bone formation, comprising administering one or more ofthe compositions described herein to a subject in need thereof.Prostaglandins have been shown to stimulate bone resorption and boneformation to increase the volume and the strength of the bone (H.Kawaguchi et. al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller etal., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Furthermore,inhibition of 15-PGDH increases callus size and mineralization afterbone fracture (Collier et. al., ORS 2017 Annual Meeting Paper No. 0190).Considering that 15-PGDH inhibits the activities of prostaglandins asmentioned in the above, the inhibition of 15-PGDH activity may lead tothe promotion of bone resorption and bone formation that are inhibitedby 15-PGDH. Thus, the inhibitors of hydroxyprostaglandin dehydrogenasedescribed herein can be effective for the promotion of bone resorptionand bone formation by inhibiting 15-PGDH activity. Thehydroxyprostaglandin dehydrogenase inhibitors provided herein can alsobe used to increase bone density, treat osteoporosis, promote healing offractures, promote healing after bone surgery or joint replacement,and/or to promote healing of bone to bone implants, bone to artificialimplants, dental implants, and bone grafts.

In another aspect, provided herein is a method of stimulating tissueregeneration by stimulating, comprising administering one or more of thecompositions described herein to a subject in need thereof.Prostaglandin PGE2 supports expansion of several types of tissue stemcells. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), aprostaglandin-degrading enzyme, potentiates tissue regeneration inmultiple organs. Studies show that inhibition of 15-PGDH increasesprostaglandin PGE2 levels in bone marrow and other tissues; accelerateshematopoietic recovery following a bone marrow transplant; promotestissue regeneration of colon and liver injury (Zhang, Y. et. al. Science2015, 348 (6240)). The hydroxyprostaglandin dehydrogenase inhibitorsprovided herein can be used for tissue regeneration by supporting theexpansion of tissue stem cells.

In another aspect, provided herein is a method of modulating cervicalripening, comprising administering one or more of the compositionsdescribed herein to a subject in need thereof. Prostaglandin E2 (PGE2)is a known cervical ripening agent that mediates EP2-receptor-signalingpathways in human cervical stromal cells; targets its own synthesis byincreasing COX-2 and PTGES expression; and decreases its metabolism byloss of its degradative enzyme 15-PGDH (Word et. Al., WO2019010482)Downregulation of 15-PGDH was also found to be crucial for PGE2-inducedcervical ripening and preterm birth. Modulation of 15-PDGH activity canbe used to modulate cervical ripening; and induce or prevent pretermlabor. The hydroxyprostaglandin dehydrogenase inhibitors provided hereincan be used to induce cervical ripening and labor, alone or incombination with another labor inducing agent.

In another aspect, provided herein is a method of promotingneuroprotection and/or stimulating neuronal regeneration, comprisingadministering one or more of the compositions described herein to asubject in need thereof. Prostaglandins, via their specific G proteincoupled receptors, have a variety of physiological functions in thecentral nervous system. The major prostaglandin, prostaglandin E2 (PGE2)can activate receptor types EP1, 2, 3, and 4. Activation of EP2 and EP4receptors can regulate adenylate cyclase and the generation of 3,5′-cyclic adenosine monophosphate (cAMP), whereas the activation of EP1and EP3 receptors can regulate Ca2+ signaling. Studies show that the EP1and EP2 receptors are expressed in neurons and microglia as well asneurons of the cerebral cortex, striatum, and hippocampus. In addition,activation of the EP2 receptor by PGE2 is involved in long-term synapticplasticity and cognitive function (Chemtob et al. Semin Perinatol. 1994February; 18(1):23-9; Yang et al., J Neurochem. 2009 January;108(1):295-304). Studies also show that following activation, differentPG E2 receptors can contribute or protect against N-methyl-D-aspartate(NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp TranslStroke Med. 2010 Jul. 8; 2(1):12). Other studies show that activation ofthe EP2 receptors protected neurons from amyloid β-peptide neurotoxicityin vitro (Echeverria et al., Eur J Neurosci. 2005 November;22(9):2199-206). Several studies suggest that the mechanism by whichPGE2 affords neuroprotection is through EP2 or EP4 receptors, as theyboth increases cAMP, followed by a protein kinase A (PKA)-dependentpathway (Echeverria et al. Eur J Neurosci. 2005 November;22(9):2199-206; McCullough et al., J Neurosci. 2004 Jan. 7;24(1):257-68). Stimulation of these receptors with PGE2 byadministration of a compound that inhibits, reduces, and/or antagonizes15-PGDH activity, such as the hydroxyprostaglandin dehydrogenaseinhibitors that can inhibit 15-PGDH described herein, can promoteneuroprotection in a subject from axonal degeneration, neuronal celldeath, and/or glia cell damage after injury, augment neuronal signalingunderlying learning and memory, stimulate neuronal regeneration afterinjury, and/or treat diseases, disorders, and/or conditions of thenervous system.

In another aspect, provided herein is a method of treating and/orpreventing a neurological disorder, a neuropsychiatric disorder, aneural injury, a neural toxicity disorder, a neuropathic pain, or aneural degenerative disorder, comprising administering one or more ofthe compositions described herein to a subject in need thereof. In someembodiments, the disease, disorder, and/or condition of the nervoussystem, which can be treated with hydroxyprostaglandin dehydrogenaseinhibitors provided herein, can include at least one of a neurologicaldisorder, a neuropsychiatric disorder, a neural injury, a neuraltoxicity disorder, a neuropathic pain, or a neural degenerativedisorder. For example, the neurological disorder can include at leastone of traumatic or toxic injuries to peripheral or cranial nerves,spinal cord or brain, such as traumatic brain injury, stroke, cerebralaneurism, and spinal cord injury. The neurological disorder can alsoinclude at least one of Alzheimer's disease, dementias related toAlzheimer's disease, Parkinson's, Lewy diffuse body diseases, seniledementia, Huntington's disease, Gilles de Ia Tourette's syndrome,multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor andsensory neuropathy, diabetic neuropathy, progressive supranuclear palsy,epilepsy, or Jakob-Creutzfieldt disease.

In some embodiments, the neural injury can be caused by or associatedwith at least one of epilepsy, cerebrovascular diseases, autoimmunediseases, sleep disorders, autonomic disorders, urinary bladderdisorders, abnormal metabolic states, disorders of the muscular system,infectious and parasitic diseases, neoplasms, endocrine diseases,nutritional and metabolic diseases, immunological diseases, diseases ofthe blood and blood-forming organs, mental disorders, diseases of thenervous system, diseases of the sense organs, diseases of thecirculatory system, diseases of the respiratory system, diseases of thedigestive system, diseases of the genitourinary system, diseases of theskin and subcutaneous tissue, diseases of the musculoskeletal system andconnective tissue, congenital anomalies, or conditions originating inthe perinatal period.

In certain embodiments, the hydroxyprostaglandin dehydrogenaseinhibitors can be administered to a subject or neurons of the subject topromote the survival, growth, development and/or function of theneurons, particularly, the central nervous system (CNS), brain,cerebral, and hippocampal neurons. In certain embodiments, thehydroxyprostaglandin dehydrogenase inhibitors can be used stimulatehippocampal neurogenesis, for the treatment of neuropsychiatric andneurodegenerative diseases, including (but not limited to)schizophrenia, major depression, bipolar disorder, normal aging,epilepsy, traumatic brain injury, post-traumatic stress disorder,Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellarataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke,radiation therapy, chronic stress, and abuse of neuro-active drugs, suchas alcohol, opiates, methamphetamine, phencyclidine, and cocaine.

In another aspect, provided herein is a method of treating and/orpreventing fibrotic or adhesion disease, disorder or condition,comprising administering one or more of the compositions describedherein to a subject in need thereof. It has been shown that inhibitorsof short-chain dehydrogenase activity, such as 15-PGDH inhibitors, canbe administered to a subject in need thereof to decrease fibroticsymptoms, such as collagen deposition, collagen accumulation, collagenfiber formation, inflammatory cytokine expression, and inflammatory cellinfiltration, and treat and/or prevent various fibrotic diseases,disorders, and conditions characterized, in whole or in part, by theexcess production of fibrous material, including excess production offibrotic material within the extracellular matrix, or the replacement ofnormal tissue elements by abnormal, non-functional, and/or excessiveaccumulation of matrix-associated components (Markowitz et. al.,WO2016/144958).

Fibrotic diseases, disorders and conditions characterized, in whole orin part, by excess production of fibrotic material can include systemicsclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis,scleroderma (including morphea, generalized morphea, or linearscleroderma), sclerodermatous graft-vs-host-disease, kidney fibrosis(including glomerular sclerosis, renal tubulointerstitial fibrosis,progressive renal disease or diabetic nephropathy), cardiac fibrosis(e.g., myocardial fibrosis), pulmonary fibrosis (e.g. pulmonaryfibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonaryfibrosis, silicosis, asbestosis, interstitial lung disease, interstitialfibrotic lung disease, and chemotherapy/radiation induced pulmonaryfibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis,pancreatitis, inflammatory bowel disease, Crohn's disease, nodularfasciitis, eosinophilic fasciitis, general fibrosis syndromecharacterized by replacement of normal muscle tissue by fibrous tissuein varying degrees, retroperitoneal fibrosis, liver fibrosis, livercirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis),drug induced ergotism, myelodysplastic syndrome, myeloproliferativesyndrome, collagenous colitis, acute fibrosis, organ specific fibrosis,and the like. The hydroxyprostaglandin dehydrogenase inhibitors providedherein can be used to treat or prevent a fibrotic disease, disorder orcondition.

The hydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to treat or prevent kidney fibrosis, including kidney fibrosisresulting from dialysis following kidney failure, catheter placement, anephropathy, glomerulosclerosis, glomerulonephritis, chronic renalinsufficiency, acute kidney injury, end stage renal disease or renalfailure, or combinations thereof.

The hydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to treat or prevent liver fibrosis, including liver fibrosisresulting from a chronic liver disease, viral induced hepatic cirrhosis,hepatitis B virus infection, hepatitis C virus infection, hepatitis Dvirus infection, schistosomiasis, primary biliary cirrhosis, alcoholicliver disease or non-alcoholic steatohepatitis (NASH), NASH associatedcirrhosis obesity, diabetes, protein malnutrition, coronary arterydisease, auto-immune hepatitis, cystic fibrosis, alpha-1-antitrypsindeficiency, primary biliary cirrhosis, drug reaction and exposure totoxins, or combinations thereof.

The hydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to treat or prevent heart fibrosis such as cardiac fibrosis,endomyocardial fibrosis, idiopathic pulmonary fibrosis, and kidneyfibrosis.

The hydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to treat or prevent systemic sclerosis.

The hydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to treat or prevent fibrotic diseases, disorders or conditionscaused by post-surgical adhesion formation.

The hydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to reduce in intensity, severity, or frequency, and/or delay onsetof one or more symptoms or features of a fibrotic disease, disorder orcondition, or other related diseases, disorders or conditions.

The hydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to decrease or reduce collagen secretion, or collagen deposition,or collagen fiber accumulation, in a tissue or organ, such as the lung,the liver, the intestines, the colon, the skin or the heart, or acombination thereof.

Studies have shown that 15-PGDH inhibition ameliorates inflammatorypathology and fibrosis in pulmonary fibrosis (Smith et. al., bioRxiv2019.12.16.878215; Barnthaler et. al., J. Allergy Clin. Immunol. 2019,145 (3), 818-833). In some embodiments, the hydroxyprostaglandindehydrogenase inhibitors described herein can be used to treat orprevent lung fibrosis, including pulmonary fibrosis, pulmonaryhypertension, chronic obstructive pulmonary disease (COPD), asthma,idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familialpulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis,carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonaryfibrosis caused by inhalation of inorganic dust, pulmonary fibrosiscaused by an infectious agent, pulmonary fibrosis caused by inhalationof noxious gases, aerosols, chemical dusts, fumes or vapors,drug-induced interstitial lung disease, or pulmonary hypertension, andcombinations thereof.

In another aspect, provided herein is a method of reducing and/orpreventing scar formation, comprising administering one or more of thecompositions described herein to a subject in need thereof. Thehydroxyprostaglandin dehydrogenase inhibitors provided herein can usedfor reducing or preventing scar formation in a subject. Thehydroxyprostaglandin dehydrogenase inhibitors provided herein can beused to reduce or prevent scar formation on skin or scleroderma.

In another aspect, provided herein is a method of treating and/orpreventing muscle disorder, muscle injury and/or muscle atrophy,comprising administering one or more of the compositions describedherein to a subject in need thereof. Studies have shown that inhibitionof PGE2 degrading enzymes such as 15-PGDH, enable muscle regenerationand muscle repair after injury (Ho et al., PNAS 2017; Dong et al., Stemcell research and therapy 2020). The inhibitors of hydroxyprostaglandindehydrogenase provided herein can be used to treat muscle disorder,muscle injury and/or muscle atrophy in a subject. In some cases, saidsubject suffering from a muscle disorder, muscle injury and/or muscleatrophy may have Duchenne muscular dystrophy (DMD), Becker musculardystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdlemuscular dystrophy, congenital muscular dystrophy, facioscapulohumeralmuscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), distalmuscular dystrophy (DD), an inherited myopathy, myotonic musculardystrophy (MDD), oculopharyngeal muscular dystrophy, distal musculardystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita,mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis(MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis,cancer cachexia, AIDS cachexia, stress induced urinary incontinence,urethral sphincter deficiency, sarcopenia, or a combination thereof.

In some embodiments, the inhibitors of hydroxyprostaglandindehydrogenase provided herein can be used to treat sarcopenia. Inanother embodiment, the inhibitors of hydroxyprostaglandin dehydrogenaseprovided herein can be used to treat diaphragmatic atrophy or limbmuscle atrophy due to the use of a mechanical ventilator. In someembodiments, the inhibitors of hydroxyprostaglandin dehydrogenaseprovided herein can be used to treat genetic disorders or neuromusculardisorders such as Spinal Muscular Atrophy (SMA). In some embodiments,the inhibitors of hydroxyprostaglandin dehydrogenase provided herein canbe used to treat ptosis, rotator cuff muscle atrophy, immobilizationrelated muscle atrophy, surgical procedure related muscle atrophy,sarcopenia, or a combination thereof.

Pharmaceutical Compositions

The inhibitors of hydroxyprostaglandin dehydrogenase can be formulatedinto pharmaceutical compositions to treat diseases and disordersdescribed herein. In some embodiments, a pharmaceutical composition maycomprise a therapeutically effective amount of one or more inhibitors ofhydroxyprostaglandin dehydrogenase provided herein.

The pharmaceutical composition described herein may be administered insuch oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,micronized compositions, granules, elixirs, tinctures, suspensions,ointments, vapors, liposomal particles, nanoparticles, syrups andemulsions. In some embodiments, the pharmaceutical composition may alsobe administered in intravenous (bolus or infusion), subcutaneousinjection, suppository, intraperitoneal, topical (e.g., dermalepidermal, transdermal), ophthalmically such as ocular eyedrop,intranasally, subcutaneous, inhalation, intramuscular or transdermal(e.g., patch) form, all using forms well known to those of ordinaryskill in the pharmaceutical arts.

In some embodiments, a compound provided herein can be administered aspart of a therapeutic regimen that comprises administering one or moresecond agents (e.g. 1, 2, 3, 4, 5, or more second agents), eithersimultaneously or sequentially with the compound provided herein. Whenadministered sequentially, the compound provided herein may beadministered before or after the one or more second agents. Whenadministered simultaneously, the compound provided herein and the one ormore second agents may be administered by the same route (e.g.injections to the same location; tablets taken orally at the same time),by a different route (e.g. a tablet taken orally while receiving anintravenous infusion), or as part of the same combination (e.g. asolution comprising a compound provided herein and one or more secondagents).

A combination treatment according to the disclosure may be effectiveover a wide dosage range. For example, in the treatment of adult humans,dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg perday, and from 5 to 40 mg per day are examples of dosages that may beused. The exact dosage will depend upon the agent selected, the route ofadministration, the form in which the compound is administered, thesubject to be treated, the body weight of the subject to be treated, andthe preference and experience of the attending physician.

EXAMPLES Example 1: Synthesis and Characterization of Compounds

In another aspect, methods of making the inhibitors described herein areprovided herein. In some cases, the inhibitors are isolated or extractedfrom one or more plants. In some cases, the inhibitors derived from theone or more plants may be further modified. In some cases, theinhibitors are further purified after isolation from the one or moreplants.

Exemplary synthesis schemes for the inhibitors with phenyl core asdescribed herein include:

Exemplary synthesis schemes for the inhibitors with 6-5 ring cores asdescribed herein include:

In some cases, synthesis schemes may be entire synthesis schemes forproducing the inhibitors provided herein. In other cases, synthesisschemes may be partial schemes for producing inhibitors provided herein.

Described herein are exemplary synthesis schemes that can be used tosynthesize the inhibitors described herein. The following abbreviationsare used:

Abbreviation Description AIBN azobisisobutyronitrile DCM dichloromethaneDIAD diisopropyl azodicarboxylate DIPEA N,N′-diisopropylethylamine DMAP4-dimethylaminopyridine DMF dimethylformamide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate HOBt hydroxybenzotriazole m-CPBAMeta-chloroperoxybenzoic acid NBS N-bromosuccinimide NCSN-chlorosuccinimide NIS N-iodosuccinimide p-TSA para-toluenesulfonicacid TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TPPtriphenylphosphine mmol Milli molar vol Volume g Gram kg Kilogram LLitre mL Milli litre ° C. Degree Celsius TLC Thin Layer ChromatographyHPLC High-performance liquid chromatography LCMS Liquid chromatography -mass spectrometry min Minutes h Hour eq Equivalents RT Room temperatureRf Retention factor RP Reversed phase NMR Nuclear magnetic resonance PpmParts per million

Synthesis of benzimidazole-5-carboxyamide Analogs with Amide Variation

Provided below is an exemplary scheme to synthesizebenzimidazole-5-carboxyamide analogs with amide variation that areinhibitors of hydroxyprostaglandin dehydrogenase.

Step-1: Synthesis of methyl 4-fluoro-3-nitrobenzoate (Int-2): To astirred solution of methyl 4-fluoro-3-nitrobenzoic acid (10 g, 54.02mmol) in DCM (100 mL) were added oxalylchloride (9.42 mL, 108.04 mmol, 2eq) and followed by the DMF (1 mL) at 0° C. The RM was stirred at 0° C.for 1 h. The reaction was monitored by TLC, after completion of thereaction, quenched with methanol (20 mL), and stirred at roomtemperature for 1 h. Then solvent was evaporated under reduced pressureand diluted with ethyl acetate (100 mL), washed with sat.NaHCO₃ solution(50 mL), and brine solution (50 mL), the organic phases are dried oversodium sulfate, filtered and concentrated under reduced pressure toobtain methyl 4-fluoro-3-nitrobenzoate (10.4 g, 96.7%) as an off whitesolid. LCMS: 75.82%, m/z=199.8 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δ 8.75(dd, J=2.20, 7.21 Hz, 1H), 8.32 (ddd, J=2.2, 4.3, 8.7 Hz, 1H), 7.39 (dd,J=8.7, 10.2 Hz, 1H), 3.97-3.99 (m, 3H).

Step-2: Synthesis of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate(Int-3), (general procedure for SNAr reactions #1): In sealed bomb; To astirred solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 50.21 mmol, 1eq) in EtOH (100 mL), 3-chloroaniline (7.68 g, 60.25 mmol, 1.2 eq) wasadded at room temperature. Steel bomb cap was tightly closed and thenresultant reaction mixture was heated to 100° C. for 16 h. The reactionwas monitored by LCMS/TLC, after completion of the reaction cooled toroom temperature, volatiles were evaporated, quenched with sat.NH₄Cl(100 mL), extracted with EtOAc (3×50 mL), combined organic extracts werewashed with brine (50 mL); dried over sodium sulfate, filtered andconcentrated in vacuo to get crude, trituration with diethyl ether (100mL) to obtained methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (8.2 g,53.24%) as a yellow solid. LCMS: 95.95%, m/z=307.1 [M+H]⁺; ¹H NMR(CDCl₃, 400 MHz): δ 9.73 (br s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.01 (dd,J=1.8, 8.9 Hz, 1H), 7.36-7.41 (m, 1H), 7.26-7.31 (m, 2H), 7.19 (d, J=8.9Hz, 2H), 3.92 (s, 3H).

Step-3: Synthesis of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate(Int-4), (general procedure for aryl nitro reduction using Fe): To astirred solution of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate(8.2 g, 26.79 mmol, 1 eq) in EtOH/water (1:1, 160 mL), iron powder(10.47 g, 187.55 mmol, 7 eq) and NH₄Cl (10.03 g, 187.55 mmol, 7 eq) wereadded at room temperature. The resultant reaction mixture was heated to100° C. for 16 h. The reaction was monitored by LCMS/TLC and aftercompletion, the reaction mixture was filtered through celite bed andwashed with EtOAc (2×100 mL). Volatiles were evaporated, quenched withsat. NaHCO₃ (100 mL), extracted with EtOAc (3×50 mL) and combinedorganic extracts were washed with brine (100 mL), dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 50%EtOAc/heptane to obtained methyl 3-amino-4-((3-chlorophenyl) amino)benzoate (7.1 g, 96.07%) as a gummy liquid. LCMS: 67.71%, m/z=277.1[M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δ 7.45-7.50 (m, 2H), 7.14-7.19 (m, 2H),6.86-6.91 (m, 2H), 6.77 (td, J=1.2, 8.8 Hz, 1H), 5.55 (br s, 1H), 3.88(s, 3H).

Step-4: Synthesis of methyl1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (Int-5): To astirred solution of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate(7.1 g, 25.72 mmol, 1 eq) and triethyl orthoformate (19.06 g, 128.62mmol, 5 eq) in 1, 4-Dioxane (80 mL) PTSA (884 mg, 5.144 mmol, 0.2 eq)was added at room temperature. The resulting reaction mixture was heatedto 100° C. for 16 h until SM was consumed as indicated by crudeLCMS/TLC. The reaction mixture was filtered through celite bed, washedwith EtOAc (2×100 mL). Volatiles were evaporated, washed with sat.NaHCO₃ (100 mL) and extracted with EtOAc (3×100 mL). The combinedorganic extracts were washed with brine (200 mL); dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 40%EtOAc/heptane to obtained methyl1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (5.8 g, 78.6%) asa pale brown solid. LCMS: 89.6%, m/z=287.2 [M+H]⁺; ¹H NMR (CDCl₃, 400MHz): δ 8.60 (d, J=1.0 Hz, 1H), 8.18 (s, 1H), 8.08 (dd, J=1.5, 8.6 Hz,1H), 7.53-7.58 (m, 3H), 7.42-7.51 (m, 2H), 3.97 (s, 3H).

Step-5: Synthesis of1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-6),general procedure for ester hydrolysis using NaOH: To a stirred solutionof methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate) (5.8 g,20.23 mmol, 1 eq) in THF/water (8:2, 60 mL) or MeOH/water (8:2, 60 mL),NaOH (1.21 g, 30.34 mmol, 1.5 eq) was added room temperature and thencontinued stirring at room temperature for 16 h. The reaction wasmonitored by crude LCMS/TLC; after consumption of the starting material,volatiles were evaporated, neutralized with 1N HCl up to pH=7. Thesolids were filtered, washed with Et₂O (200 mL) and dried in vacuo toobtain 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid (4.5 g,81.66%) as a pale brown solid. LCMS: 99.58%, m/z=273.1 [M+H]⁺; ¹H NMR(DMSO-d₆, 500 MHz): δ 12.44-13.20 (m, 1H), 8.73 (s, 1H), 8.32 (s, 1H),7.96 (br d, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.65-7.73 (m, 3H), 7.58-7.61(m, 1H).

Step 6: General procedure for amide coupling using HATU: To a stirredsolution of Int-6 (1 eq) in DMF (10 v) under inert atmosphere were addedHATU (1.5 eq), Amine (1.2 eq) was added at 0° C. To this stirredsolution N, N′-diisopropylethylamine (3 eq) was added at 0° C. and thencontinued for stirring at room temperature for 16 h. The reaction wasmonitored by crude LCMS/TLC; after consumption of the starting material,the reaction mixture was quenched with ice water (10 mL) and extractedwith EtOAc (2×15 mL). The combined organic extracts were washed with icewater (2×10 mL) and brine (10 mL); dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 40% EtOAc/heptane,followed by prep-HPLC to obtain the products shown in Scheme 1.

Synthesis of (3-aminopyrrolidin-1-yl) (1-(3-chlorophenyl)-1H-benzo [d]imidazol-5-yl) methanone

Provided below is an exemplary scheme to synthesize(3-aminopyrrolidin-1-yl) (1-(3-chlorophenyl)-1H-benzo [d] imidazol-5-yl)methanone that are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 2

Step-1: Synthesis of tert-butyl(1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)carbamate(Int-7): Int-6 (400 mg, 1.47 mmol) was reacted with 3-Boc aminopyrrolidine (326 mg, 1.76 mmol, 1.2 eq) using the general procedure foramide coupling using HATU described above to afford tert-butyl(1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)carbamate(280 mg, 43%) as a pale yellow liquid. LCMS: 81.8%, m/z=−441.2 [M+H]⁺;¹H NMR (DMSO-d₆ 400 MHz): δ 8.76 (s, 1H), 7.85-7.98 (m, 2H), 7.49-7.74(m, 4H), 7.20-7.29 ((m, 1H), 3.87-4.12 (m, 1H), 3.59-3.68 (m, 2H),3.08-3.35 (m, 2H), 2.81-2.89 (m, 1H), 2.65-2.73 (m, 1H), 1.94-2.09 (m,1H), 1.69-1.89 (m, 1H), 1.30-1.40 (m, 9H).

Step-2: Synthesis of(3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone(MF-PGDH-051): To a stirred solution of Int-7 (280 mg, 0.63 mmol, 1 eq)in DCM (5 mL), cooled to 0° C. and added 4N HCl in 1, 4-Dioxane (5 mL),allowed to warm to room temperature then continued stirring at roomtemperature for 16 h. The reaction was monitored by LCMS/TLC; afterconsumption of the starting material, the reaction mixture wasconcentrated and dissolved in water and washed with EtOAc (20 mL), thenthe aq. layer was basified with sat. NaHCO₃ solution and extracted withEtOAc (3×20 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to afford(3-aminopyrrolidin-1-yl) (1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone (120 mg, 57% yield) as an off-white solid. LCMS: m/z=341.2[M+H]⁺.

Synthesis of1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide(MF-PGDH-064)

Provided below is an exemplary scheme to synthesize1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamidethat are inhibitors of hydroxyprostaglandin dehydrogenase.

Step-1: Synthesis of1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide(MF-PGDH-064): A stirred solution of1-(3-chlorophenyl)-N-cyclopropyl-1H-benzo[d]imidazole-5-carboxamide (200mg, 0.641 mmol, 1 eq) in DMF (3 mL) was cooled to 0° C. and NaH (60% inmineral oil) (24 mg, 0.96 mmol, 1.5 eq) added. After stirring at 0° C.for 20 min, methyl iodide (136.05 mg, 0.961 mmol, 1.5 eq) was added at0° C. and allowed to warm to room temperature stirred for 6 h. Thereaction was monitored by LCMS/TLC; after consumption of the startingmaterial the reaction mixture was quenched with sat. ammonium chloridesolution (20 mL) and extracted with EtOAc (2×20 mL). The combinedorganic extracts were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 40%EtOAc/heptane, followed by prep-HPLC purification to obtain1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide(14.31 mg, 6.84% yield) as a brown liquid. LCMS: m/z=326.1 [M+H]⁺.

Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090)

Provided below is an exemplary scheme to synthesize1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl) pyrrolidin-3-onethat are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 4

Step-1 and 2: Synthesis of1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one(MF-PGDH-090): To a stirred solution of Int-6 (100 mg, 0.367 mmol, 1 eq)in DCM (2 mL), cool to 0° C. and added Oxalyl chloride (92.73 mg, 0.735mmol, 2.0 eq), DMF (0.1 mL), then stirred at 0° C. for 30 min. Thereaction was monitored by TLC; after completion of the starting materialthe reaction mixture was concentrated and followed to the next step.Crude was dissolved in DCM (2 mL), cooled to 0° C., added pyrrolidone(53.60 mg, 121.5 mmol, 1.2 eq), warmed to room temperature thencontinued stirring at room temperature for 16 h. The reaction wasmonitored by crude LCMS/TLC; after consumption of the starting materialthe reaction mixture was concentrated in vacuo to obtain the crude. Thecrude was purified through prep-HPLC purification to obtain1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl) pyrrolidin-3-one(MF-PGDH-090, 4.8 mg, 3.85% yield) as a brown liquid.

Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide(MF-PGDH-102)

Provided below is an exemplary scheme to synthesize1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide that areinhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 5

Step-1: Synthesis of1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102): Toa stirred solution of Int-6 (200 mg, 0.733 mmol, 1 eq) in DMF (5 mL)under inert atmosphere were added HATU (416 mg, 1.093 mmol, 1.5 eq),NH₄Cl (196.33 mg, 3.669 mmol, 5.0 eq) was added at 0° C. To this stirredsolution N, N′-diisopropylethylamine (282 mg, 2.177 mmol, 3.0 eq) wasadded at 0° C. and then continued for stirring at room temperature for16 h. The reaction was monitored by crude LCMS/TLC; after completion ofthe starting material the reaction mixture was quenched with ice water(10 mL), extracted with EtOAc (2×15 mL). The combined organic extractswere washed with ice water (2×10 mL) and brine (10 mL); dried oversodium sulfate, filtered and concentrated in vacuo to obtained1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (138.52 mg,69.51%) as an off-white solid. LCMS: m/z=272.1 [M+H]⁺.

Synthesis of Benzimidazoles Analogs with 2-Substituents

Provided below is an exemplary scheme to synthesize benzimidazolesanalogs with 2-substituents that are inhibitors of hydroxyprostaglandindehydrogenase.

Scheme 6

Step-1: Synthesis of 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid(Int-1): In sealed bomb; To a stirred solution of4-fluoro-3-nitrobenzoic acid (5 g, 27.02 mmol, 1 eq) in ethanol (100 mL)at room temperature, were added meta chloro aniline (4.18 g, 32.96 mmol,1.22 eq) followed by the potassium carbonate (1.86 g, 13.51 mmol, 0.5eq) and then heated to 80° C. for 16 h. The reaction was monitored byTLC, after completion of the reaction, cooled to room temperature andfiltered; the solid was washed with ethanol and dried to obtain4-((3-chlorophenyl)amino)-3-nitrobenzoic acid (5.2 g, 65.8% yield) as anoff white solid. LCMS: m/z=293.0[M+H]⁺.

Step-2: Synthesis of(4-((3-chlorophenyl)amino)-3-nitrophenyl)(piperidin-1-yl)methanone(Int-2): To a stirred solution of Int-1 (4.5 g, 15.41 mmol, 1 eq) in DCM(45 mL) was added oxalyl chloride (5.83 g, 46.23 mmol, 3 eq) drop-wiseat 0° C., and then continued stirring at 0° C. for 1 h, The reaction wasmonitored by TLC. After completion of the reaction it was cooled to roomtemperature and volatiles were evaporated. This was dissolved in DCM (45mL) and to this stirred solution piperidine (1.57 g, 18.49 mmol, 1.2 eq)was added, stirred at room temperature for 5 h, concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 5% MeOH/DCM to obtain (4-((3-chlorophenyl)amino)-3-nitrophenyl)(piperidin-1-yl) methanone (5.7 g, 89% yield) as ayellow solid. LCMS: 87.89%, m/z=360.0[M+H]⁺.

Step-3: Synthesis of(3-amino-4-((3-chlorophenyl)amino)phenyl)(piperidin-1-yl)methanone(Int-3): To a stirred solution of Int-2 (7 g, 19.44 mmol, 1 eq) inEtOH:water (1:1, 120 mL), Iron powder (7.6 g, 136.11 mmol, 7 eq) andNH₄Cl (7.4 g, 136.11 mmol, 7 eq) were added at room temperature. Theresultant reaction mixture was heated to 90° C. for 16 h. The reactionwas monitored by TLC; after consumption of the starting material, thereaction mixture was filtered through celite bed and washed with EtOAc(2×50 mL). Volatiles were evaporated, quenched with water (100 mL),extracted with EtOAc (3×100 mL). The combined organic extracts werewashed with brine (50 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was triturated withdiethyl ether (20 mL) to afford (3-amino-4-((3-chlorophenyl)amino)phenyl)(piperidin-1-yl)methanone (5 g, 77.60%) as a gummy liquid. LCMS:m/z=330.0 [M+H]⁺.

Step-4A: Synthesis of ethyl1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazole-2-carboxylate(MF-PGDH-027): In a sealed tube; the stirred solution of Int-3 (200 mg,0.606 mmol, 1 eq), ethyl glyoxalate (186.2 mg, 1.823 mmol, 3 eq) andPTSA (20 mg, 0.116 mmol, 0.2 eq) was added at room temperature. Theresulting reaction mixture was heated to 70° C. for 16 h. The reactionwas monitored by TLC; after completion of the starting material, cooledto room temperature and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 50%EtOAc/heptane, followed by Prep-HPLC purification to obtain MF-PGDH-027(18.82 mg, 7.55% yield) as an off-white solid.

Step-4B: Synthesis of ethyl2-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)acetate(MF-PGDH-030): To a stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq)in DMF (3 mL), ethyl (E)-3-amino-3-ethoxyacrylate (355 mg, 1.818 mmol, 3eq) was added at room temperature. The resulting reaction mixture washeated to 100° C. for 16 h. The reaction was monitored by TLC; aftercompletion of the starting material, cooled to room temperature andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 50% EtOAc/heptane,followed by Prep-HPLC purification to obtain MF-PGDH-030 (35.4 mg,13.7%) as an off-white solid.

Step-4C: Synthesis of MF-PGDH-091 (general procedure for esterhydrolysis using LiOH): To a stirred solution of MF-PGDH-30 (1 g, 2.35mmol, 1 eq) in THF:water (1:1, 10 mL) at 0° C., LiOH·H₂O (235 mg, 4.7mmol, 2 eq) was added at 0° C. The resultant reaction mixture wasstirred at room temperature for 12 h. reaction was monitored by TLC;after completion of the starting material, cooled to room temperatureand concentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 50% EtOAc/heptane,followed by Prep-HPLC purification to afford MF-PGDH-091 (20.38 mg,2.9%) as an off-white solid. LCMS: m/z=354.2 [M+H]⁺.

Step-4D: Synthesis of methyl4-((2-((3-chlorophenyl)amino)-5-(piperidine-1-carbonyl) phenyl)amino)-4-oxobutanoate (Int-4): Int-3 (500 mg, 1.51 mmol, 1 eq) wassubjected to the general procedure for amide coupling with HATU toafford methyl4-((2-((3-chlorophenyl)amino)-5-(piperidine-1-carbonyl)phenyl)amino)-4-oxobutanoate(600 mg, 89.1%) as an off-white solid. LCMS: m/z=444.1 [M+H]⁺.

Step-4E: Synthesis of ethyl3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanoate(MF-PGDH-033) and3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanoicacid (MF-PGDH-034): To a stirred solution of Int-4 (1 g, 2.252 mmol, 1eq) in DCE (20 mL), TFA (10 mL) was added under inert atmosphere at 0°C. Slowly warmed to room temperature and then heated to 80° C. for 16 h.The reaction was monitored by TLC; after completion of the startingmaterial the reaction mixture was cooled to room temperature and dilutedwith ice water (20 mL). Neutralized with 10% NaHCO₃ solution andextracted with EtOAc (2×50 mL). The combined organic extracts werewashed with ice water (2×10 mL) and brine (10 mL); dried over sodiumsulfate, filtered and concentrated in vacuo to get crude. The crude waspurified through Prep-HPLC purification to obtain MF-PGDH-033 (68.36 mg)and MF-PGDH-034 (33.41 mg) as off-white solids.

Step-4F: Synthesis of3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanamide(MF-PGDH-035): To a stirred solution of MF-PGDH-034 (200 mg, 2.252 mmol,1 eq) in steel bomb, aqueous ammonia (10 mL) in MeOH was added at 0° C.The resulting reaction mixture was slowly warmed to room temperature andthen heated to 80° C. for 16 h. The reaction was monitored by TLC; aftercompletion of the starting material the reaction mixture was cooled toroom temperature and concentrated in vacuo to get crude. The crude waspurified through Prep-HPLC purification to obtain MF-PGDH-035 (33.27 mg,17.3% yield) as an off-white solid.

Synthesis of Benzimidazole-5-carboxamide Analogs with Aryl/Alkyl/AmideVariation

Provided below is an exemplary scheme to synthesizeBenzimidazole-5-carboxyamide analogs with Aryl/alkyl/Amide variationthat are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 7

The synthesis of Int-1 is described in 1a, Scheme 1 above.

Step-2: Synthesis of methyl 4-((4-methoxyphenyl)amino)-3-nitrobenzoate(Int-2): Methyl 4-fluoro-3-nitrobenzoate (10 g, 50.21 mmol, 1 eq) inEtOH (100 mL) was converted to Int-2 using the general procedure forSNAr reactions #1, with p-anisidine (7.68 g, 60.25 mmol, 1.2 eq) toafford methyl 4-((4-methoxyphenyl)amino)-3-nitrobenzoate (8.2 g, 53.24%)as a yellow solid. LCMS: 96.47%, m/z=303.1 [M+H]⁺.

Step-3: Synthesis of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate(Int-3): Methyl-(4-methoxyphenyl)amino)-3-nitrobenzoate (8.09 g, 26.79mmol) was converted to methyl 3-amino-4-((4-methoxyphenyl) amino)benzoate (7.1 g, 96.07%) using the general procedure for aryl nitroreduction using Fe to afford Int-3 as a gummy liquid. LCMS: 91.32%,m/z=273.2 [M+H]⁺.

Step-4: Synthesis of methyl1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate/methyl2-cyclopropyl-1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate(Int-4a/4b): To a stirred solution of methyl3-amino-4-((4-methoxyphenyl)amino)benzoate (7.02 g, 25.72 mmol, 1 eq)and triethyl orthoformate/cyclopropinaldehyde (128.62 mmol, 5 eq) in 1,4-Dioxane (80 mL)/DMF, PTSA (884 mg, 5.144 mmol, 0.2 eq)/Na₂S₂O₃ (1 eq)was added at room temperature. The resulting reaction mixture was heatedto 90° C. for 16 h until consumption of SM by crude LCMS/TLC. Thereaction mixture was filtered through celite bed and washed with EtOAc(2×100 mL). Volatiles were evaporated, washed with sat. NaHCO₃ (100 mL)and extracted with EtOAc (3×100 mL). The combined organic extracts werewashed with brine (200 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 40% EtOAc/heptane toobtained methyl 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate,Int-4a (78.6% yield, m/z=283.3 [M+H]⁺) and methyl2-cyclopropyl-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(Int-4b)(53.40% yield, m/z=323.33[M+H]⁺).

Step-5: Synthesis of1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Int-5a)/2-cyclopropyl-1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylicacid (Int-5b): Int-4a/4b (1 eq) was hydrolyzed using the generalprocedure for ester hydrolysis with NaOH to afford Int-5a (4.5 g, 81.66%yield, LCMS: m/z=269.2 [M+H]⁺), and Int-5b (230 mg, 64.5% yield, LCMS:m/z=309.0 [M+H]⁺) as a pale brown solid.

Step-6: Synthesis of MF-DH-008, MF-DH-009, and MF-DH-021: Int-5a/5b weresubjected to the general procedure for amide coupling with HATU toafford MF-DH-008, MF-DH-009, and MF-DH-021.

Synthesis of Benzimidazole-5-carboxyamide Analogs with Aryl/AmideVariation

Provided below is an exemplary scheme to synthesizebenzimidazole-5-carboxyamide analogs with Aryl/alkyl/Amide variationthat are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 8

The synthesis of Int-1 is described in Scheme 1.

Step-2: Synthesis of Int-2; general procedure for SNAr reaction #2: To astirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 12.51 mmol,1 eq) in EtOH (100 mL) in a sealed bomb,5-methoxypyridin-2-amine/3-chloro-4-methoxyaniline (1.2 eq) and K₂CO₃(1.726 g, 1 eq) were added at room temperature. The steel bomb wastightly sealed and the reaction mixture was heated to 100° C. for 16 h.The reaction was monitored by LCMS/TLC. Upon completion, the reactionmixture was cooled to room temperature and concentrated. The residue wasquenched with sat.NH₄Cl (100 mL) and extracted with EtOAc (3×50 mL), andthe combined organic extracts were washed with brine (50 mL), dried oversodium sulfate, filtered, and concentrated in vacuo to afford the crude.The crude was triturated with diethyl ether (100 mL) to afford Int-2a(50.5% yield, LCMS: m/z=304.1[M+H]⁺) for MF-PGDH-22 and MF-DH-141 asyellow solids.

Int-1 was converted to Int-2b (51.0% yield, m/z=337.2[M+H]⁺) forMF-PGDH-24 and MF-PGDH-61.

Int-1 was converted to Int-2c (59.0% yield, LCMS: m/z=317.1[M+H]⁺) forMF-PGDH-62 using the general procedure for SNAr #1.

Step-3: Synthesis of Int-3a, Int-3b, and Int-3c was accomplished usingthe general procedure for aryl nitro reduction to afford Int-3a (82.3%yield, LCMS: m/z=274.1 [M+H]⁺), Int-3b (79.2% yield, LCMS: m/z=307.1[M+H]⁺) and Int-3c (80.0% yield, LCMS: m/z=287.2 [M+H]⁺) as gummyliquids.

Step-4: Synthesis of Int-4a, Int-4b, and Int-4c: To a stirred solutionof Int-3a/Int-3b/Int-3c (1 eq) and triethyl orthoformate (19.06 g,128.62 mmol, 5 eq) in 1, 4-Dioxane (80 mL)/DMF, PTSA (884 mg, 0.2 eq)was added at room temperature. The resulting reaction mixture was heatedto 90° C. for 16 h until consumption of SM by crude LCMS/TLC. Thereaction mixture was filtered through celite bed, washed with EtOAc(2×50 mL). Volatiles were evaporated, washed with sat. NaHCO₃ (20 mL);extracted with EtOAc (3×30 mL), combined organic extracts were washedwith brine (30 mL); dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 40% EtOAc/heptane to obtain Int-4a (32.7%yield, LCMS: m/z=287.2 [M+H]⁺), Int-4b (73.0% yield, LCMS: m/z=317.1[M+H]⁺), and Int-4c (83.0% yield, LCMS: m/z=297.0 [M+H]⁺) as pale brownsolids.

Step-5: Synthesis of Int-5a, Int-5b, and Int-5c: Using the generalprocedure for ester hydrolysis with NaOH, Int-4a, Int-4b, and Int-4cwere converted to Int-5a (65.2% yield, LCMS: m/z=270.1 [M+H]⁺), Int-5b(70.5% yield, LCMS: m/z=303.2 [M+H]⁺) and Int-5c (81.4% yield, LCMS:m/z=282.1 [M+H]⁺), all obtained as pale brown solids.

Step-6: Int-5 was coupled to the appropriate amines using the generalprocedure for amide couplings with HATU to afford MF-PGDH-022,MF-PGDH-024, MF-PGDH-062 and MF-DH-141.

Step-7: Synthesis of(1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone:To a stirred solution of(1-(3-chloro-4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone,MF-PGDH-024 (200 mg, 0.54 mmol, 1 eq) in CH₂Cl₂ (10 mL) under inertatmosphere; BBr₃ (1.62 mL, 1.62 mmol, 3.0 eq, 1M in CH₂Cl₂) was added at0° C. and stirred at room temperature for 16 h. The reaction wasmonitored by crude LCMS/TLC; after consumption of the starting material,the reaction mixture was quenched with MeOH (10 mL), evaporated todryness and then quenched with saturated NaHCO₃ solution (5 mL). It wasextracted with EtOAc (2×15 mL), combined organic extracts were washedwith brine (10 mL), dried over sodium sulfate, filtered and concentratedin vacuo to afford the crude which was purified by prep-HPLC to afford1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone,MF-PGDH-061 (120 mg, 63%) as off white solid.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs withAmide/Aryl/Hetero Aryl Variation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl/Hetero Arylvariations that are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 9 and Scheme 10

Step 1, Scheme 9: As shown in Scheme 9, Int-1 was subjected to amidecoupling with the appropriate amine using HATU as described previouslyto afford Int-2.

Piperidin-1-yl (1H-pyrrolo[2,3-b]pyridin-5-yl)methanone: (950 mg, Yield:79%); LCMS: m/z=230.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ=11.84 (s, 1H),8.23 (s, 1H), 7.98 (s, 1H), 7.56 (d, J=1.83 Hz, 1H), 6.51 (d, J=1.89 Hz,1H), 3.67-3.38 (m, 4H), 1.68-1.43 (m, 6H).

(4-fluoropiperidin-1-yl) (1H-pyrrolo[2,3-b]pyridin-5-yl)methanone: (2.17g, Yield: 69%); LCMS: 88.5%, m/z=248.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ=11.83 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.65 (d, J=1.84 Hz, 1H),6.78 (d, J=1.86 Hz, 1H), 3.76-3.35 (m, 4H), 1.98-1.54 (m, 4H).

(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone:(1.15 g, Yield: 69%); LCMS: 85.2%) m/z=282 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ=13.11 (br s, 1H), 12.35 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H),7.80 (s, 1H), 5.03-4.80 (m, 1H), 3.82-3.33 (m, 4H), 2.04-1.64 (m, 4H).

Step-2, Scheme 9: General Buchwald procedure for synthesis of(MF-PGDH-071 and MF-DH-123, 124): In sealed tube, a stirring solution ofpiperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone/(4-fluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-2) (0.65 mmol, 1 eq) in dioxane (15 mL) under inert atmosphere,Cs₂CO₃ (422 mg, 1.3 mmol, 2.0 eq) and the corresponding chloro/bromoarene (1.2 eq) were added at room temperature. Argon gas was purged for15 min then Xantphos (75.14 mg, 0.13 mmol, 0.2 eq) and Pd₂(dba)₃ (59.47mg, 0.065 mmol, 0.1 eq),) were added under argon atmosphere. Sealed tubecap was tightly closed and the resultant reaction mixture was heated to100° C. for 16 h. The reaction was monitored by crude LCMS/TLC; aftercompletion of the reaction, the reaction mixture was quenched with satd.NH₄Cl (10 mL), filtered through celite bed, washed with EtOAc (10 mL).The mixture was extracted with EtOAc (2×10 mL), combined organicextracts were washed with brine (10 mL), dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 70%EtOAc/heptanes, followed by Prep-HPLC purification afforded MF-PGDH-071and MF-DH-123, 124.

Step 1, Scheme 10: General procedure for chlorination using NCS.Synthesis of 3-chloro-1H-pyrrolo [2,3-b]pyridine-5-carboxylic acid(Int-2, Scheme 10): To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-1) (1 g, 6.17 mmol) in DMF (10 v)under inert atmosphere was added NCS (906 mg, 6.68 mmol) at 40° C. Theresultant reaction mixture was heated to 60° C. for 4 h. The reactionwas monitored by crude LCMS/TLC; after completion of the startingmaterial the reaction mixture was quenched with ice water (20 mL),solids were filtered, washed with diethyl ether (3×10 mL). The crudeproduct was azeotroped with toluene (2×10 mL) and then dried for 2 h toafford 3-chloro-1H-pyrrolo [2,3-b]pyridine-5-carboxylic acid (Int-2) aslight brown solid (850 mg, Yield: 70%). LCMS: 88.2%) m/z=195.0 [M−H]⁻;¹H NMR (500 MHz, DMSO-d₆) δ=13.18 (br s, 1H), 12.37 (s, 1H), 8.84 (s,1H), 8.45 (s, 1H), 7.82 (s, 1H).

Step 2, Scheme 9 and Step 3, Scheme 10: General Ullmann couplingprocedure: To a stirred solution of Int-2 (Scheme 9)/Int-3 (Scheme 10)(0.7 mmol, 1 eq) in Dioxane (100 mL), heteroaryl bromide (1.2 eq) 2.0eq. K₃PO₄, 0.2 eq. CuI, 0.2 eq. trans-dimethylcyclohexane-1,2-diaminewere added at room temperature. Reaction mixture was purged with argongas for 15 min and then continued the reaction at 100° C. for 16 h. Thereaction was monitored by TLC and after completion of the reaction,quenched with sat.NH₄Cl solution (10 mL), and stirred at roomtemperature for 1 h. The solvent was evaporated under reduced pressureand diluted with ethyl acetate (10 mL), washed with sat. NaHCO₃ solution(50 mL), and brine solution (50 mL) and the organic phase dried oversodium sulfate, filtered and concentrated under reduced pressure toafford crude product which was further purified by prep-HPLC to affordthe final products MF-PGDH-014, MF-PGDH-067, MF-PGDH-069, MF-PGDH-070,MF-PGDH-073, MF-PGDH-074, MF-PGDH-075, MF-PGDH-076, MF-DH-128,MF-DH-129, MF-DH-131, MF-DH-132, MF-DH-133, MF-DH-134, MF-DH-135,MF-DH-139, MF-DH-140, MF-DH-145 and MF-DH-157.

Synthesis of Azabenzimidazole Analogs

Provided below is an exemplary scheme to synthesize Azabenzimidazoleanalogs that are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 11

Step-1: Synthesis of Int-1: 6-Chloro-5-nitronicotinate (7 g, 32.31 mmol,1 eq) and 3-Cl/4-methoxyaniline (1 eq) were subjected to SNAr #2conditions to afford Int-1a (Ar=3-Cl phenyl, 95.2% yield, LCMS:m/z=308.2[M+H]⁺) as a yellow solid and Int-1b (Ar=4-OMe phenyl, 87.6%yield, LCMS: 96.0%, m/z=304.2[M+H]⁺) as a pale yellow solid.

Step-2: Synthesis of Int-2: Methyl-6-((4-methoxyphenyl)amino)-5-nitronicotinate/methyl-6-((3-chlorophenyl)amino)-5-nitronicotinate(Int-1) was subjected to the general procedure for aryl nitro reductionwith Fe. The crude was purified through silica gel column chromatographyusing 60% EtOAc/heptane to obtain Int-2a (Ar=3-Cl phenyl, 97% yield,LCMS: m/z=278.2[M+H]⁺) as a yellow solid and Int-2b (Ar=4-OMe phenyl,77% yield, LCMS: m/z=272.4 [M+H]⁺) as a pale yellow solid.

Step-3: Synthesis of Int-3 (general procedure for PTSA catalyzed ringclosure to form imidazole): To a stirred solution ofmethyl-5-amino-6-((4-methoxyphenyl)amino)nicotinate/methyl-5-amino-6-((3-chlorophenyl)amino)nicotinate (Int-2) (1 g, 1 eq) and triethyl orthoformate (5 eq) indioxane (20 mL), PTSA (0.2 eq) was added at room temperature. Theresulting reaction mixture was heated to 100° C. for 16 h. The reactionwas monitored by crude LCMS/TLC; after consumption of the startingmaterial, reaction mixture was filtered through celite bed, washed withEtOAc (2×50 mL). Volatiles were evaporated, quenched with saturatedNaHCO₃ solution (20 mL) and extracted with EtOAc (3×50 mL). The combinedorganic extracts were washed with brine (20 mL), dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 50%EtOAc/heptane to obtain Int-3a (Ar=3-Cl phenyl, 83% yield, LCMS:m/z=288.2 [M+H]⁺) as a yellow solid and Int-3b (Ar=4-OMe phenyl, 71%yield, LCMS: m/z=284.2[M+H]⁺) as a pale yellow solid.

Step-4: Synthesis of Int-4, general procedure for ester hydrolysis withLiOH: To a stirred solution of methyl3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate/methyl3-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-3) (1 g,1 eq) in THF/water (1:1, 20 mL) or MeOH/water (1:1, 20 mL), LiOH (2.5eq) was added at room temperature and the resulting reaction mixture wasstirred at room temperature for 16 h. The reaction was monitored bycrude LCMS/TLC; upon completion, the reaction mixture was concentratedand neutralized with 1N HCl. The resulting solids were filtered, washedwith Et₂O (50 mL), and dried in vacuo to obtain Int-4a (Ar=3-Cl phenyl,65% yield, LCMS: m/z=274.2 [M+H]⁺) as an off-white solid and Int-4b(Ar=4-OMe phenyl, 90.5% yield, LCMS: m/z=270.1 [M+H]⁺) as an off-whitesolid.

Step-5: Synthesis of MF-PGDH-020, MF-PGDH-077, MF-PGDH-078, MF-PGDH-079and MF-PGDH-138: Int-4 was subjected to amide coupling with theappropriate amine using HATU as described previously to afford the crudewhich was purified through silica gel column chromatography using 40%EtOAc:heptane/5% MeOH:CH2Cl2 followed by Prep-HPLC purification toobtain MF-PGDH-020, MF-PGDH-077, MF-PGDH-078, MF-PGDH-079 andMF-PGDH-138 as an off-white solid. The compounds in Scheme 11 above weresynthesized by this procedure.

Synthesis of 2-Substituted azabenzimidazole Analogs MF-DH-115 andMF-DH-116

Provided below is an exemplary scheme to synthesize 2-substitutedazabenzimidazole analogs that are inhibitors of hydroxyprostaglandindehydrogenase.

Scheme 12

Step-1: Synthesis methyl2-amino-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(Int-3): To a stirred solution of methyl5-amino-6-((4-methoxyphenyl)amino)nicotinate (1 g, 3.54 mmol, 1 eq) inMeOH/water (1:1, 40 mL), cyanogen bromide (1.1 g, 10.63 mmol, 3 eq) wasadded at 0° C. The reaction mixture was slowly warmed to roomtemperature then heated to 80° C. for 16 h. The reaction was monitoredby crude LCMS/TLC; after completion of the reaction it was cooled toroom temperature and quenched with water (10 mL), extracted with EtOAc(3×50 mL), combined organic extracts were washed with brine (50 mL);dried over sodium sulfate, filtered and concentrated in vacuo to obtainmethyl2-amino-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(1.08 g, 99%) as a gummy liquid. LCMS: 80.63%, m/z=299.2[M+H]⁺.

Step-2: Synthesis methyl2-acetamido-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(Int-4): To a stirred solution of Int-3 (800 mg, 2.68 mmol, 1 eq) in DCM(8 mL), triethylamine (829 mg, 8.05 mmol, 3 eq) was added at 0° C. Itwas stirred for 10 min at 0° C. and then acetic anhydride (821 mg, 8.05mmol, 3 eq) was added. The reaction mixture was allowed to warm to roomtemperature then stirred for 16 h. The reaction was monitored by crudeLCMS/TLC; after completion of the reaction it was quenched with icewater (10 mL), extracted with EtOAc (3×50 mL); combined organic extractswere washed with brine (50 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to afford the crude. The crude was purifiedthrough silica gel column chromatography using 20% EtOAc/heptane toafford methyl2-acetamido-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(550 mg, 60.3%) as an off-white solid. LCMS: m/z=341.0[M+H]⁺.

Step-3: Synthesis of2-acetamido-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (Int-5): Int-4 (450 mg, 1.32 mmol, 1 eq) was subjected to thegeneral procedure for ester hydrolysis with NaOH to afford2-acetamido-3-(4-methoxyphenyl)-3H-imidazo [4,5-b]pyridine-6-carboxylicacid (400 mg, 96%) as a pale brown solid. LCMS: m/z=327.0[M+H]⁺.

Step-4: Synthesis of MF-DH-116: Int-5 (470 mg, 1.44 mmol, 1 eq) wassubjected to amide coupling with 4-fluoro piperidine (241 mg, 1.73 mmol,1.2 eq) using HATU as described previously. The crude was purifiedthrough silica gel column chromatography using 5% MeOH/DCM followed byPrep-HPLC purification to obtain MF-DH-116 (12.57 mg, 2.12%) as anoff-white solid.

Step-5: Synthesis of MF-DH-115: To a stirred solution of MF-DH-116 (350mg, 0.85 mmol, 1 eq) in methanol (5 mL) under inert atmosphere was addedK₂CO₃ (235 mg, 1.70 mmol, 2.0 eq) at room temperature and then continuedstirring at room temperature for 16 h. The reaction was monitored bycrude LCMS/TLC; after consumption of the starting material, the reactionmixture was filtered and the filtrate was concentrated in vacuo toafford the crude. The crude was purified through silica gel columnchromatography using 5% MeOH/DCM followed by Prep-HPLC purification toobtain MF-DH-115 (12.46 mg, 3.96%) as an off-white solid.

Synthesis of Benzamide Analogs

Provided below is an exemplary scheme to synthesize benzamide analogsthat are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 13

Step-1: Synthesis of (4-(hydroxymethyl)phenyl)(piperidin-1-yl) methanone(Int-1): To a stirring solution of 4-(hydroxymethyl)benzoic acid (2 g,13.15 mmol, 1 eq) and piperidine (1.12 g, 13.5 mol, 1 eq) in CH₂Cl₂ (20mL) under inert atmosphere; EDCI (3.82 g, 19.72 mol, 1.2 eq), HOBt (2.13g, 15.78 mol, 1.2 eq) were added at 0° C. To this stirred solution N,N′-diisopropylethylamine (373 mL, 2.14 mol, 3 eq) was added at 0° C. andthen continued stirring at room temperature for 16 h. The reaction wasmonitored by crude LCMS/TLC; after consumption of starting materials,the reaction mixture was quenched with ice water (50 mL) and extractedwith EtOAc (2×50 mL). The combined organic extracts were washed with icewater (2×20 mL) and brine (20 mL), dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 40% EtOAc/heptane toafford Int-1 (1.6 g, 57.1%) as a pale-yellow solid. LCMS: m/z=220.1[M+H]⁺.

Step-2: Synthesis of MF-PGDH-036, MF-PGDH-037 and MF-PGDH-039: To astirring solution of Int-1 (250 mg, 1.13 mmol, 1 eq) and2-bromophenol/2-Chlorophenol/2-chlorothiophenol (1.1 eq) in THF (10 mL)under inert atmosphere; TPP (446 mg, 1.7 mol, 1.5 eq) followed by DIAD(460 mg, 1.07 mmol, 1.5 eq) in THF (5 mL) were added sequentially andthen continued stirring at room temperature for 16 h. The reaction wasmonitored by crude LCMS/TLC; after completion of the reaction, thereaction mixture was quenched with ice water (10 mL), extracted withEtOAc (2×10 mL). The combined organic extracts were washed with brine(10 mL), dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was purified through silica gel columnchromatography using 40% EtOAc/heptanes followed by Prep-HPLCpurification to obtain MF-PGDH-036 (Yield: 2.05%), MF-PGDH-037 (Yield:2.1%), and MF-PGDH-039 (Yield: 2.2%), as an off-white solid.

Synthesis of(4-(((2-chlorophenyl)sulfonyl)methyl)phenylpiperidin-1-yl)methanone(MF-PGDH-040)

Provided below is an exemplary scheme to synthesize(4-(((2-chlorophenyl)sulfonyl)methyl)phenylpiperidin-1-yl)methanone thatis an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 14

To a stirring solution of MF-PGDH-39 (from Scheme 13) (200 mg, 0.578mmol, 1 eq) in CH₂Cl₂ (15 mL), m-CPBA (196.1 mg, 1.15 mmol, 2 eq) wasadded and then continued stirring at room temperature for 16 h. Anadditional aliquot of m-CPBA was added (1 equiv.). The reaction wasmonitored by crude LCMS/TLC; after consumption of the starting material,the reaction mixture was quenched with ice water (10 mL), extracted withCH₂Cl₂ (2×10 mL). The combined organic extracts were washed with brine(10 mL); dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was purified through silica gel columnchromatography using 40% EtOAc/heptane followed by Prep-HPLCpurification to obtained(4-(((2-chlorophenyl)sulfonyl)methyl)phenyl)(piperidin-1-yl)methanone(MF-PGDH-040)(21.1 mg, 9.6%) as a brown liquid.

Synthesis of(4-(((2-chlorophenyl)sulfinyl)methyl)phenyl(piperidin-1-yl)methanone(MF-PGDH-045)

Provided below is an exemplary scheme to synthesize(4-(((2-chlorophenyl)sulfinyl)methyl)phenyl)(piperidin-1-yl)methanonethat is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 15

To a stirring solution of MF-PGDH-39 (50 mg, 0.144 mmol, 1 eq) inCH₃CN:water, NaIO4 (61.99 mg, 0.289 mmol, 2 eq) was added and thencontinued stirring at room temperature for 4 h. The reaction wasmonitored by crude LCMS/TLC; after consumption of starting material, thereaction mixture was quenched with ice water (10 mL) and extracted withEtOAc (2×10 mL). The combined organic extracts were washed with brine(10 mL), dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was purified through silica gel columnchromatography using 40% EtOAc/heptane followed by Prep-HPLCpurification to afford 35.8 mg of MF-PGDH-045 as a brown liquid.

Synthesis of MF-PGDH-38, MF-PGDH-098, MF-DH-118, and MF-DH-121

Provided below is an exemplary scheme to synthesize inhibitors ofhydroxyprostaglandin dehydrogenase labeled as MF-PGDH-38, MF-PGDH-098,MF-DH-118, and MF-DH-121 in Scheme 16 below.

Scheme 16

Scheme 16A Step-1: Synthesis of methyl 4-(bromomethyl)-3-methoxybenzoate(Int-1): To a stirring solution of methyl3-methoxy-4-methylbenzoate/methyl 5-methylpicolinate (2.5 g, 13.87 mmol,1 eq) in CHCl₃ (20 mL) under inert atmosphere, NBS (2.96 g, 16.66 mol,1.2 eq) and AIBN (0.45 g, 2.74 mol, 0.2 eq) were added at roomtemperature and then the resultant reaction mixture was heated to refluxfor 16 h. The reaction was monitored by crude LCMS/TLC; afterconsumption of the starting material, the reaction mixture was quenchedwith saturated Na₂S₂O₃ (10 mL) and extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with ice water (2×30 mL) and brine(20 mL), dried over sodium sulfate, filtered and concentrated in vacuoto afford the crude. The crude was purified through silica gel columnchromatography using 30% EtOAc/heptane to obtain methyl4-(bromomethyl)-3-methoxybenzoate (Int-1) (2.0 g, 55.7%) as off-whitesolid. MS: m/z=261.1 [M+2]⁺.

Scheme 16A Step-2: Synthesis of Int-2: To a stirring solution of Int-1(500 mg, 1.93 mmol, 1 eq), 2-chloro phenol (1 eq) in DMF (10 mL) underinert atmosphere, K₂CO₃ (1.5 eq) was added at room temperature and thenheated to reflux for 16 h. The reaction was monitored by crude LCMS/TLC;after consumption of the starting material, the reaction mixture wasquenched with ice water (10 mL), extracted with EtOAc (3×15 mL). Thecombined organic extracts were washed with ice water (2×10 mL) and brine(20 mL), dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was purified through silica gel columnchromatography using 15% EtOAc/heptane to obtain Int-2 (430 mg; Yield:71.83%)) as off-white solid. LCMS: 91.35%: m/z=307.3 [M+H]⁺.

Scheme 16A Step-3: Synthesis of Int-3: Int-2 was hydrolyzed using thegeneral procedure for ester hydrolysis with LiOH to afford Int-3 (Yield:58.7%) as a pale brown solid. LCMS: m/z=293.2 [M+H]⁺.

Scheme 16A Step-4: Synthesis of MF-PGDH-038, MF-DH-118: Int-3 (200 mg, 1eq) was coupled with piperidine/4-fluoro piperidine (1.2 eq) using HATUas the coupling agent as described previously to afford MF-PGDH-038,MF-DH-118 as off-white solids.

Scheme 16B Step-1: Synthesis of methyl 5-(bromomethyl)picolinate(Int-1): methyl 5-methylpicolinate was brominated using the generalprocedure for bromination described earlier using NBS to afford Int-1(Yield: 52%) as off-white solid. LCMS: m/z=232.9 [M+2H]⁺.

Scheme 16B Step-2: Synthesis of methyl5-((2-chlorophenoxy)methyl)picolinate (Int-2): Int-1 was converted toInt-2 using the procedure for substitution reaction described earlier(Scheme 16A) with 2-chlorophenol to afford Int-2 (Yield: 66%) as paleyellow solid. LCMS: m/z=278.1 [M+H]⁺.

Scheme 16B Step-3: Synthesis of 4-((2-chlorophenoxy)methyl)benzoic acid(Int-3): Int-2 was hydrolyzed using the general procedure for esterhydrolysis with LiOH to afford Int-3 (Yield: 84%) as off-white solid.LCMS: m/z=264.1 [M+H]⁺.

Scheme 16B Step-4: Synthesis of(5-((2-chlorophenoxy)methyl)pyridin-2-yl(4-fluoropiperidin-1-yl)methanone(MF-DH-121): Int-3 was coupled with 4-fluoro piperidine using HATU asthe coupling agent as described previously to afford MF-DH-121 (Yield:61%) as off-white solids. LCMS: 99.96%, MS: m/z=349.0 [M+H]⁺.

Synthesis of MF-PGDH-095. MF-PGDH-096 and MF-PGDH-097

Provided below is an exemplary scheme to synthesize inhibitors ofhydroxyprostaglandin dehydrogenase labeled as MF-PGDH-095, MF-PGDH-0%and MF-DH-097 in Scheme 17 below.

Scheme 17

Step-1: To a stirred solution of bromo compound MF-PGDH-036 (5 g, 0.013mol, 1 eq) and corresponding Bis(pinacolato)diboron (5.1 g, 0.02 mol,1.5 eq.) in 1, 4-dioxane (5 V, 50 mL/mmol), KOAc (3.82 g, 0.04 mmol, 3eq.) was added and purged with Argon for 15 min. To this solution, PdCl₂(dppf)·DCM (1 g, 0.0013 mmol, 0.1 eq.) was added and purged with Argonfor another 10 min. The resulting reaction mixture was stirred at 90° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughCelite and evaporated to dryness. The residue was taken in ethylacetate, washed with water, followed by brine, dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude productwas purified by column chromatography to afford 2.82 g (51%) of Int-1;LCMS: m/z=422.2 [M+H]⁺, 340.2 [M+H]⁺.

Step-2: To a stirred solution of the aryl/heteroaryl bromide (2.1 mmol,1 eq.) and Int-1 (2.52 mmol, 1.2 eq.) in 1, 4-dioxane:water (3:1, 4.96mL/mmol), Na₂CO₃ (6.5 mmol, 3 eq.) was added and purged with Argon for15 min. To this solution, Pd(PPh₃)₄ (0.21 mmol, 0.1 eq.) was added andpurged with Argon for another 10 min. The resulting reaction mixture wasstirred at 90° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was filteredthrough celite and evaporated to dryness. The residue was taken in ethylacetate, washed with water, followed by brine, dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude productwas purified by column chromatography followed by preparative HPLC to toobtain MF-PGDH-095, MF-PGDH-096, and MF-PGDH-097 as off-white solids.

Synthesis of MF-PGDH-041, MF-PGDH-042, MF-PGDH-087, MF-PGDH-088 andMF-PGDH-089

Provided below is an exemplary scheme to synthesize inhibitors ofhydroxyprostaglandin dehydrogenase labeled as MF-PGDH-041, MF-PGDH-042and MF-DH-087 in Scheme 18 below.

Scheme 18

Step-1: Synthesis of Int-1: 4-nitrobenzoic acid (2 g, 1 eq) andpiperidine/4,4-difluoropiperidine (1.5 eq) were coupled using HATU asdescribed previously to afford Int-1a (X, X′=F, 85% yield, LCMS:m/z=271.1[M+H]⁺) and Int-1b (X, X′=H, 91% yield, LCMS: m/z=235.1[M+H]⁺).

Step-2: Synthesis of Int-2: Int-1 (1 eq) was converted to Int-2 usingthe general procedure for reduction of aryl nitro with Fe describedabove to afford Int-2a (X, X′=F, 51.7% yield, LCMS: m/z=240.1 [M+H]⁺)and Int-2b: (X, X′=H, 53.5% yield, LCMS: m/z=205.2 [M+H]⁺).

Step-3: Synthesis of Int-3: Int-2 (1 eq) and 2-methoxy phenyl/2-Chlorophenyl/3-methoxyphenyl carboxylic acid (0.7 eq) were coupled using HATUas described previously to afford MF-PGDH-041, MF-PGDH-087, MF-PGDH-088,and MF-PGDH-089 as off-white solids.

Step-4: Synthesis of MF-PGDH-042 (general procedure for N-methylation ofamide): To a stirred solution of MF-PGDH-041 (140 mg, 0.414 mmol, 1 eq)in THF (5 mL), NaH (60% in mineral oil) (30 mg, 0.625 mmol, 1.5 eq) wasadded at 0° C. to room temperature for 1 h. To this stirred suspension,Mel ((88.18 mg, 0.625 mmol, 1.5 eq) was added and then resultingreaction mixture was stirred for 6 h. The reaction was monitored bycrude LCMS/TLC; after consumption of the starting material, reactionmixture was quenched with saturated NH₄Cl (10 ml), extracted with EtOAc(2×50 mL). Combined organic extracts were washed with brine (20 mL);dried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 50% EtOAc/heptane followed by prep-HPLCpurification to obtain MF-PGDH-042 (24.42 mg, 16.71%) as a pale brownsolid.

Synthesis of MF-PGDH-043, and MF-PGDH-044

Provided below is an exemplary scheme to synthesize inhibitors ofhydroxyprostaglandin dehydrogenase labeled as MF-PGDH-043 and MF-DH-044in Scheme 19 below.

Scheme 19

Step-1: Synthesis of methyl 4-(piperidine-1-carbonyl) benzoate (Int-1):4-(methoxycarbonyl)benzoic acid (2 g, 11.09 mmol, 1 eq) and piperidine(1.3 mL, 13.31 mmol, 1.5 eq) in DMF (20 mL) were coupled using HATU asdescribed previously to afford Int-1 (2.6 g, yield: 92%) as pale yellowsolid. MS: m/z=248.1 [M+H]⁺.

Step-2: Synthesis 4-(piperidine-1-carbonyl) benzoic acid (Int-2): Int-1(2.8 g) was hydrolyzed using the general procedure for ester hydrolysiswith NaOH to afford Int-2 (1.8 g, yield: 58%) as off-white solid. MS:m/z=234.0 [M+H]⁺.

Step-3: Synthesis N-(2-methoxyphenyl)-4-(piperidine-1-carbonyl)benzamide (MF-PGDH-043): 4-(piperidine-1-carbonyl)benzoic acid (800 mg,3.43 mmol, 1 eq) was coupled with 2-methoxy aniline (0.5 mL, 4.12 mol,1.2 eq) using HATU (2 g, 5.14 mol, 1.5 eq), as described previously toafford MF-PGDH-043 (1 g, yield: 90%) as a pale yellow solid.

Step-4: N-(2-methoxyphenyl)-N-methyl-4-(piperidine-1-carbonyl) benzamide(MF-PGDH-044): MF-PGDH-043 (300 mg) was methylated with Mel using thegeneral procedure for N-methylation of amide to afford MF-PGDH-044(64.44 mg, 23.69%), as a pale brown solid.

Synthesis of indoles MF-PGDH-004 and MF-PGDH-005

Provided below is an exemplary scheme to synthesize inhibitors ofhydroxyprostaglandin dehydrogenase labeled as MF-PGDH-004 and MF-DH-005in Scheme 20 below.

Scheme 20

Step-1: Synthesis of Int-1: For R=Cl in Scheme 1 above,1H-indole-5-carboxylic acid (2 g) was converted to Int-1 (2.3 g; Yield:95%)) using the general procedure for chlorination with NCS. MS:m/z=196.01 [M+H]⁺.

Step-2: Synthesis of Int-2: Int-1/1H-indole-5-carboxylic acid wascoupled with piperidine using the general procedure of amide couplingwith HATU to afford Int-2a (R=H, 71% yield, MS: m/z=229.1 [M+H]⁺) andInt-2b (R=Cl, 68% yield, MS: m/z=263.6 [M+H]⁺).

Step-3: Synthesis of MF-PGDH-004, and MF-PGDH-005: To a stirred solutionof Int-2a/Int-2b (1 eq) in DMF (10 mL), 3-chloroiodobenzene (1.2 eq),K₂CO₃ (2 eq) were added at room temperature. The reaction mixture waspurged with argon gas for 15 min. To this stirred solution CuI (0.2 eq),and trans-dimethyl cyclohexane-1,2-diamine (0.2 eq) was added and thencontinued stirring at 100° C. for 16 h. The reaction was monitored byTLC, after completion of starting material, quenched with sat.NH₄Clsolution (10 mL) filtered, washed with EtOAc. Extract with EtOAc, washedwith ice water (2×30 mL) and brine solution (50 mL), the organic phasewas dried over sodium sulfate, filtered and concentrated under reducedpressure to obtain the crude which was further purified by Prep-HPLC toafford MF-PGDH-004 and MF-PGDH-005 as off-white solids.

Synthesis of MF-PGDH-053, and MF-PGDH-054

Provided below is an exemplary scheme to synthesize inhibitors ofhydroxyprostaglandin dehydrogenase labeled as MF-PGDH-053 and MF-DH-054in Scheme 21 below,

Scheme 21

Step-1: Synthesis of methyl 3-bromo-H-indole-6-carboxylate (Int-1): To astirring solution of methyl 1H-indole-6-carboxylate (2 g, 11.42 mmol, 1eq) in DMF (40 mL), NBS (3.04 g, 17.14 mmol, 1.5 eq) was added thenstirred at room temperature for 2 h. The reaction was monitored by crudeLCMS/TLC; after completion of the reaction, the mixture was quenchedwith ice water (10 mL) and extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with ice water (2×30 mL) and brine (20 mL),dried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 30% EtOAc/heptane to obtain Int-1 (1.51 g, 53%), asa pale brown solid. MS: m/z=256.1 [M+2]⁺.

Step-2: Synthesis of methyl 3-(3-chlorophenyl)-1H-indole-&-carboxylate(Int-2), general procedure for Suzuki coupling: To a stirring solutionof methyl 3-bromo-1H-indole-6-carboxylate (2.3 g, 9.05 mmol, 1 eq.),(3-chlorophenyl)boronic acid (2.11 g, 13.58 mmol, 1.5 eq.) in 1,4-dioxane:water (3:1, 20 mL), Na₂CO₃ (2.39 g, 22.63 mmol, 2.5 eq) wasadded and then the mixture was purged with Argon for 15 min. To thissolution, Pd(PPh₃)₄ (1.04 g, 0.90 mmol, 0.1 eq) was added under argon.The resulting reaction mixture was stirred at 80° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was filtered through celite andevaporated to dryness. The residue was taken in ethyl acetate, washedwith water, followed by brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude product was purified bycolumn chromatography using 40% EtOAc/heptane to obtain Int-2 (550 mg,22%) as a brown solid. MS: m/z=287.1 [M+2]⁺.

Step-3: Synthesis of 3-(3-chlorophenyl)-1H-indole-6-carboxylic acid(Int-3): Using the general procedure for ester hydrolysis with LiOH,methyl 3-(3-chlorophenyl)-1H-indole-6-carboxylate (550 mg) was convertedto Int-3 (500 mg, 95.7%), as a pale brown solid. MS: m/z=270.1 [M−H]⁺.

Step-4: Synthesis of(3-(3-chlorophenyl)-1H-indol-6-yl)(piperidin-1-yl)methanone,MF-PGDH-053: Using the general procedure for amide coupling with HATU,3-(3-chlorophenyl)-1H-indole-6-carboxylic acid (500 mg) was converted toMF-PGDH-053 as an off-white solid.

Step-5: Synthesis of(3-(3-chlorophenyl)-1-methyl-1H-indol-6-yl)(piperidin-1-yl)methanone,MF-PGDH-054: To a stirred solution of MF-PGDH-053 (20 ng, 0.059 mmol, 1eq) in THF (0.2 mL), NaH (60% in mineral oil) (3 mg, 0.11 mmol, 2 eq)was added at 0° C. to room temperature for 1 h. To this stirredsuspension of Mel ((16 ng, 0.11 mmol, 2 eq) was added and then resultingreaction mixture was stirred for 2 h. The reaction was monitored bycrude LCMS/TLC; after consumption of the starting material, the reactionmixture was quenched with saturated NH₄Cl (10 ml) and extracted withEtOAc (2×20 mL). Combined organic extracts were washed with brine (10mL), dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 50% EtOAc/heptane followed by prep-HPLCpurification to obtain MF-PGDH-054 (16.94 mg, 81.4%), as an off whitesolid.

Synthesis of(1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone.MF-PGDH-057

Provided below is an exemplary scheme to synthesize(1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone,MF-PGDH-057 that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 22

Step-1: Synthesis of 1,2,3,4-tetrahydroquinoline-6-carboxylic acid(Int-1): Using the general procedure for ester hydrolysis with NaOH,methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (1 g) was converted toInt-1 (800 mg, 86.9%), as a brown solid. MS: m/z=178.1 [M+H]⁺.

Step-2: Synthesis ofpiperidin-1-yl(1,2,3,4-tetrahydroquinolin-6-yl)methanone (Int-2): Usingthe general procedure for amide coupling with HATU,1,2,3,4-tetrahydroquinoline-6-carboxylic acid (800 mg) was converted toInt-2 (309 mg, 48%), as a brown solid. MS: m/z=245.2 [M+H]⁺.

Step-3: Synthesis of(1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone,MF-PGDH-057: To a stirring solution ofpiperidin-1-yl(1,2,3,4-tetrahydroquinolin-6-yl)methanone (200 mg, 0.819mmol, 1 eq.), 1-chloro-3-iodobenzene (234 mg, 0.983 mmol, 1.2 eq.) in 1,4-dioxane (4 mL), Cs₂CO₃ (800 mg, 2.45 mmol, 3 eq) was added and thenpurged with argon for 15 min. To this solution, Pd₂(dba)₃ (37.5 mg,0.0409 mmol, 0.1 eq) and xantphos (47.37 mg, 0.0819 mmol, 0.1 eq) wasadded and purged with Argon for another 10 min. The resulting reactionmixture was stirred at 90° C. for 16 h. The progress of the reaction wasmonitored by LCMS/TLC. After completion of the reaction, the mixture wasfiltered through celite and evaporated to dryness. The residue was takenin ethyl acetate, washed with water, followed by brine, dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtainthe crude. The crude was purified through prep-HPLC to affordMF-PGDH-057 (20.4 mg, 7.0%), as an off-white solid.

Synthesis of1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one,MF-PGDH-058

Provided below is an exemplary scheme to synthesize1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one,MF-PGDH-058, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 23

Step-1: Synthesis of6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (Int-1): Usingthe general procedure for amide coupling with HATU,2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (1.5 g) was coupledwith piperidine (806 mg, 9.46 mmol, 1.2 eq) to obtain Int-1 (1.7 g,84.1%), as a brown solid. MS: m/z=259.1 [M+H]⁺.

Step-2: Synthesis of1-(3-chlorophenyl)-6-(piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one,MF-PGDH-058: 6-(Piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one(200 mg, 0.775 mmol, 1 eq.) and 1-chloro-3-iodobenzene (277 mg, 1.162mmol, 1.5 eq.) were subjected to the general procedure for Ullmanncoupling. The crude was purified through prep-HPLC to afford MF-PGDH-058(23.5 mg, 8.2%), as an off-white solid.

Synthesis of(1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone,MF-PGDH-006

Provided below is an exemplary scheme to synthesize(1-(3-chlorophenyl)-1H-indazol-5-yl)(piperidin-1-yl)methanone,MF-PGDH-006, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 24

Step-1: Synthesis of (1H-indazol-5-yl)(piperidin-1-yl)methanone (Int-1):Using the general procedure for amide coupling with HATU,1H-indazole-5-carboxylic acid (500 mg) was converted to Int-1 (610 mg,86.28%), obtained as a brown solid. MS: m/z=230.1 [M+H]⁺.

Step-2: Synthesis of MF-PGDH-006: To a stirring solution of(1H-indazol-5-yl)(piperidin-1-yl)methanone (610 mg, 2.66 mmol, 1 eq.)and 1-chloro-3-iodobenzene (623 mg, 2.66 mmol, 1 eq.) in DMF (5 mL),K₂CO₃ (734 mg, 5.32 mmol, 2 eq) was added and then purged with Argon for15 min. To this solution, copper iodide (101 mg, 0.532 mmol, 0.2 eq) andtrans-N′-dimethylcyclohexane-1,2-diamine (126 mg, 0.532 mmol, 0.2 eq)was added under argon and purged another 10 min. The resulting reactionmixture was heated at 90° C. for 16 h. The progress of the reaction wasmonitored by LCMS/TLC. After completion of the reaction, the reactionmixture was filtered through celite and evaporated to dryness. Theresidue was taken in ethyl acetate, washed with water, followed bybrine, dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain the crude. The crude was purified through prep-HPLCto afford MF-PGDH-006 (40 mg, 4.41%), as a gummy liquid.

Synthesis of(3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone,MF-PGDH-007

Provided below is an exemplary scheme to synthesize(3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone,MF-PGDH-007, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 25

Step-1: Synthesis of methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate(Int-1): To a stirring solution of methylimidazo[1,2-a]pyridine-7-carboxylate (1 g, 5.68 mmol, 1 eq) in ethanol(10 mL), sodium acetate (931 mg, 11.36 mol, 2 eq), KBr (675 mg, 5.68mmol, 1 eq), followed by bromine (897 mg, 11.36 mmol, 2 eq) were addedat 0° C. and then the mixture was allowed to warm to room temperaturefor 1 h. The reaction was monitored by crude LCMS/TLC; after completionof the reaction, the mixture was quenched with saturated Na₂S₂O₃ (10 mL)and extracted with EtOAc (2×20 mL). The combined organic extracts werewashed with ice water (2×30 mL) and brine (20 mL); dried over sodiumsulfate, filtered and concentrated in vacuo to obtain Int-1 (900 mg,62%), as a pale brown solid. MS: m/z=256.1 [M+H]⁺.

Step-2: Synthesis of3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (Int-2):Using the general procedure for Suzuki coupling, methyl3-bromoimidazo[1,2-a]pyridine-7-carboxylate (600 mg, 2.38 mmol, 1 eq.)and (3-chlorophenyl)boronic acid (371 mg, 2.38 mmol, 1 eq.) were coupledto afford Int-2 (150 mg, 23%), as a brown solid. MS: m/z=273.1 [M+H]⁺.

Step-3: Synthesis of(3-(3-chlorophenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanoneMF-PGDH-007: Using the general procedure for amide coupling with HATU,3-(3-chlorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (150 mg) wasconverted to MF-PGDH-007 (29.28 mg, 15.7%), as an off-white solid.

Synthesis of(1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-Yl)methanone,MF-PGDH-011

Provided below is an exemplary scheme to synthesize(1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone,MF-PGDH-011, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 26

Step-1: Synthesis of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate(Int-1): To a stirring solution of methyl 4-fluoro-3-nitrobenzoate (2.5g, 13.50 mmol, 1 eq) in ethanol (25 mL), 4-methoxyaniline (1.72 g, 13.50mol, 1 eq) was added at room temperature and then heated to 80° C. for16 h. The reaction was monitored by crude LCMS/TLC; after completion ofthe reaction, the mixture was filtered to obtain Int-1 (2.10 g, 56.5%),as a pale brown solid. MS: m/z=307.1 [M+H]⁺.

Step-2: Synthesis of methyl 3-amino-4-((3-chlorophenyl) amino) benzoate(Int-2): Using the general procedure for aryl nitro reduction using Fe,Int-1 (2 g) was converted to Int-2 (1.20 g, 66.6%) which was obtained asa gummy liquid. MS: m/z=277.2 [M+H]⁺.

Step-3: Synthesis of methyl1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (Int-3): Toa stirred solution of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate(700 mg, 2.545 mmol, 1 eq), NaNO₂ (175 mg, 2,545 mmol, 1 eq) inTHF:water (1:1, 10 mL) under inert atmosphere, 6N H₂SO₄ (2 mL) wasslowly added at 0° C. for 15 min and then gradually brought to roomtemperature and then heated to reflux for 12 h. The reaction wasmonitored by crude TLC; after completion of the reaction, the mixturewas quenched with saturated NaHCO₃ (10 mL) and extracted with EtOAc(2×20 mL). The combined organic extracts were washed with ice water(2×30 mL) and brine (20 mL); dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 30% EtOAc/heptane toafford Int-3 (300 mg, yield: 41.26%) as an off-white solid. MS:m/z=288.1 [M+H]⁺.

Step-4: Synthesis of(1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone,MF-PGDH-011: To a stirred solution of methyl1-(3-chlorophenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (300 mg,1.045 mmol, 1 eq) in toluene (7 mL), piperidine (107 mg, 1.256 mmol, 1.2eq) followed by trimethyl aluminum (1.5 mL, 5.22 mmol, 5 eq) was addedslowly at 0° C. and then slowly heated to 50° C. for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was quenched with water (5 mL) and extracted with EtOAc (2×30mL). The combined organic extracts were washed with ice water (2×30 mL)and brine (20 mL), dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude. The crude was purified through prep-HPLCto afford MF-PGDH-011 (161.2 mg, 45.29%), as an off-white solid.

Synthesis of(3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanoneMF-PGDH-012

Provided below is an exemplary scheme to synthesize(3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone,MF-PGDH-012, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 27

Step-1: Synthesis of(3-bromopyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone (Int-1):Using the general procedure for amide coupling with HATU,3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (500 mg) was coupledwith piperidine (212 mg, 2.49 mmol, 1.2 eq) to obtain Int-1 (309 mg,48%), as a brown solid. MS: m/z=310.1 [M+2H]⁺.

Step-2: Synthesis of(3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanoneMF-PGDH-012: Using the general procedure for Suzuki coupling,(3-bromopyrazolo[1,5-a]pyrimidin-6-yl)(piperidin-1-yl)methanone (300 mg,0.97 mmol, 1 eq.) and (3-chlorophenyl)boronic acid (227 mg, 1.455 mmol,1.5 eq.) were coupled to afford MF-PGDH-012 (32.78 mg, 9.9%), as anoff-white solid.

Synthesis of(4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneMF-DH-150 and(3-chloro-4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-ylmethanoneMF-DH-151

Provided below is an exemplary scheme to synthesize(4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone,MF-DH-150, and(3-chloro-4-methyl-1-(pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone,MF-DH-151, which are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 28

Step-1: Synthesis of Int-1: A solution of1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (500 mg, 2.83 mmol, 1 eq) inDMF (15 mL), was converted to Int-1 (450 mg; Yield: 75.37%) as gummyliquid, using the general procedure for chlorination with NCS. MS:m/z=212.2 [M+H]⁺.

Step-2: Synthesis of Int-2: Int-1 (300 mg, 1.43 mmol, 1 eq) wassubjected to the general procedure for amide coupling using HATU toafford Int-2 (250 mg, 62%) as a brown liquid. MS: m/z=278.1 [M+H]⁺.

Step-3: Synthesis of MF-DH-150, and MF-DH-151: Using the generalprocedure for Ullmann coupling, Int-2 (1 eq) and 2-bromopyrazine (1.2eq) were converted to MF-DH-150 (35.7% yield) and MF-DH-151 (6.1% yield)which were isolated as off-white solids.

Synthesis of(4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanoneMF-DH-161

Provided below is an exemplary scheme to synthesize(4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone,MF-PGDH-012, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 29

Step-1: Synthesis of methyl1-(pyrazin-2-yl)-1-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate(Int-1): In sealed tube; a stirring solution of methyl2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (SM) (300mg, 1.16 mmol, 1 eq) in dioxane (15 mL) under inert atmosphere, Cs₂CO₃(1.130 & 3.47 mmol, 3.0 eq) and 2-bromopyrazine (220 mg, 1.38 mmol, 1.2eq) were added at room temperature. Argon gas was purged for 15 min thenXantphos (133.7 mg, 0.234 mmol, 0.2 eq) and Pd₂(dba)₃ (105.8 mg, 0.115mmol, 0.1 eq) were added under argon atmosphere. Sealed tube cap wastightly closed and the resultant reaction mixture was heated to 100° C.for 16 h. The reaction was monitored by crude LCMS/TLC; after completionof the reaction, the mixture was quenched with saturated NH₄Cl (10 mL),filtered through celite bed and washed with EtOAc (10 mL). The mixturewas extracted with EtOAc (2×10 mL), combined organic extracts werewashed with brine (10 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 70% EtOAc/heptanes,afforded Int-1 (220 mg, 56.4%). MS: m/z=338.1 [M+H]⁺.

Step-2: Synthesis of1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (Int-2): Int-1 (220 mg, 0.652 mmol, 1 eq) in methanol: water (1:1,10 mL) was subjected to the general procedure for ester hydrolysis withNaOH to afford Int-2 (120 mg, 57.1%), as a brown solid. MS: m/z=324.2[M+H]⁺.

Step-3: Synthesis of(4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone(MF-DH-161): A stirred solution of Int-2 (120 mg, 0.372 mmol, 1 eq) inDMF (5 v) was subjected to the general procedure for amide couplingusing HATU to afford MF-DH-161 (17.0% yield) as a semi solid.

Synthesis of(4,4-dimethyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)(4-fluoropiperidin-1-yl)methanoneMF-DH-160;((4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanoneMF-DH-162; and((4-fluoropiperidin-1-yl)(1-(pyrimidin-5-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanoneMF-DH-164

Provided below is an exemplary scheme to synthesize(4,4-dimethyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)(4-fluoropiperidin-1-yl)methanone,(MF-DH-160);((4-fluoropiperidin-1-yl)(4-methyl-1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone,(MF-DH-162); and((4-fluoropiperidin-1-yl)(1-(pyrimidin-5-yl)-1,2,3,4-tetrahydroquinolin-6-yl)methanone,(MF-DH-164), which are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 30

Step-1: Synthesis of Int-1: SM (1 g, 5.00 mmol, 1 eq) in methanol: water(1:1, 10 mL) was subjected to the general procedure for ester hydrolysiswith NaOH to Int-1a (R, R′=CH₃, 86.9% yield, MS: 206.1 [M+H]⁺), Int-1 b(R=H, R′=CH₃, 74.0% yield, MS: 192.1 [M+H]⁺) and Int-1c (R, R′=H, 73.4%yield, MS: 176.1 [M−H]⁻.

Step-2: Synthesis of (Int-2): A stirred solution of Int-1 (1.563 mmol, 1eq) in DMF (10 mL) was subjected to the general procedure for amidecoupling using HATU to afford Int-2a (R, R′=CH₃, 800 mg, 86.9% yield,MS: 291.1 [M+H]⁺), Int-2b (R=H, R′=CH₃, 650 mg, 75.9% yield, MS: 277.1[M+H]⁺) and Int-2c (R, R′=H, 73.4% yield, MS: 263.1 [M−H]⁻) as colorlessliquids.

Step-3: Synthesis of MF-DH-160, MF-DH-162 and MF-DH-164 (generalprocedure for Buchwald coupling): To a stirring solution of Int-2a/2b/2c(1.26 mmol, 1 eq.), 2-bromo pyrazine/5-bromopyridine (1.2 eq.) in 1,4-dioxane (4 mL), Cs₂CO₃ (3 eq) was added and then purged with argon for15 min. To this solution, Pd₂(dba)₃ (0.1 eq) and xantphos (0.1 eq) wasadded and purged with Argon for another 10 min. The resulting reactionmixture was stirred at 90° C. for 16 h. An extractive workup led to thecrude which was purified by column chromatography followed by prep-HPLCto afford MF-DH-160 (16.7% yield), MF-DH-162 (7.5% yield), and MF-DH-164(18.6% yield) as off-white solid/semi solids.

Synthesis of(3-chloro-1-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanoneMF-DH-167;(3-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanoneMF-DH-168; and(3-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanoneMF-DH-191

Provided below is an exemplary scheme to synthesize(3-chloro-1-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone,MF-DH-167;(3-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone,MF-DH-168; and(3-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone,MF-DH-191, which are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 31

Step-1: Synthesis of Int-1: 1 H-pyrrolo[2,3-b]pyridine-5-carboxylic acid(1 g, 6.16 mmol, 1 eq) was converted to Int-1 (850 mg; Yield: 70.1%)) aslight yellow solid using the general procedure for chlorination withNCS. MS: m/z=197.01 [M+H]⁺.

Step-2: Synthesis of Int-2: A stirring solution of SM/Int-1 (1 g, 5.12mmol, 1 eq) in DMF (10 mL) was subjected to the general procedure foramide coupling using HATU to afford Int-2 (1.1 g, 76%) as a brown solid.MS: m/z=282.2 [M+H]⁺.

Step-3: General procedure for Synthesis of MF-DH-167 and MF-DH-168,MF-DH-191: To a stirred solution of Int-2 (1 eq) in dioxane (10 mL),5-methyl-2-bromopyrazine/3-methyl-2-bromopyrazine/4-bromo anisole (1.2mmol, 1.2 eq), K₃PO₄ (630 mg, 3 mmol, 3 eq) were added at roomtemperature. The reaction mixture was purged with argon gas for 15 min.To this stirred solution CuI (38.1 mg, 0.2 mmol, 0.2 eq), andtrans-dimethyl cyclohexane-1,2-diamine (28.44 mg, 0.2 mmol, 0.2 eq) wasadded and then continued stirring at 100° C. for 16 h. The reaction wasmonitored by TLC and after complete consumption of starting material,quenched with sat. NH₄Cl solution (10 mL) filtered, washed with EtOAc.This was extracted with EtOAc, washed with ice water (2×30 mL) and brine(50 mL) and the organic phases dried over sodium sulfate, filtered andconcentrated under reduced pressure to obtain the crude. This wasfurther purified by prep-HPLC to afford MF-DH-167 (16.5% yield),MF-DH-168 (9.5% yield), and MF-DH-191 (16.9% yield) as off-white solids.

Synthesis of(4-fluoropiperidin-1-yl)(4-(pyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanoneMF-DH-159;(4-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanoneMF-DH-207; and(4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanoneMF-DH-209

Provided below is an exemplary scheme to synthesize(4-fluoropiperidin-1-yl)(4-(pyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone,MF-DH-159;(4-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone,MF-DH-207; and(4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone,MF-DH-209, which are inhibitors of hydroxyprostaglandin dehydrogenase.

Scheme 32

Step-1: Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylicacid (Int-1): Methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate(500 mg, 2.59 mmol, 1 eq) in THF: water (1:1, 10 mL) was subjected tothe general procedure for ester hydrolysis with NaOH to afford Int-1(300 mg, 64.7%) as a brown solid. Same reaction was repeated on 500 mgscale afforded 310 mg of Int-1. MS: m/z=179.9 [M+H]⁺.

Step-2: Synthesis of(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(piperidin-1-yl)methanone/(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(4-fluoropiperidin-1-yl)methanone(Int-2): A stirred solution of Int-1 (1.67 mmol, 1 eq) in DMF (10 mL)was subjected to the general procedure for amide coupling using HATU toafford the crude. The crude was purified through silica gel columnchromatography to obtain Int-2a (X=H, 95% yield, MS: m/z=247.1 [M+H]⁺)and Int-2b (X=F, 63.3% yield, MS; m/z=265.1 [M+H]⁺).

Step-3: Synthesis of(1-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-6-yl)(piperidin-1-yl)methanone,MF-DH-159, MF-DH-207, and MF-DH-209: Using the general procedure forBuchwald coupling, Int-2 (0.56 mmol, 1 eq.) and2-bromopyrazine/5-Bromobenzo[d][1,3]dioxole/4-bromoanisole (1.2 eq.)were converted to MF-DH-159 (5.48% yield), MF-DH-207 (30.3% yield), andMF-DH-209 (2.2% yield) which were isolated after purification asoff-white solids.

Synthesis of(1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone(MF-DH-203)

Provided below is an exemplary scheme to synthesize(1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone,MF-DH-203, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 33

Step-1: Synthesis of methyl 4-(tert-butylamino)-3-nitrobenzoate (Int-1):To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 12.56mmol, 1 eq) in EtOH (100 mL), t-Butylamine (918 mg, 12.56 mmol, 1 eq)was added at room temperature in a steel bomb. The cap was tightlyclosed and the resultant reaction mixture was heated to 100° C. for 16h. The reaction was monitored by LCMS/TLC and after completion of thereaction, was cooled to room temperature. The volatiles were evaporated,quenched with sat.NH₄Cl (100 mL), extracted with EtOAc (3×50 mL) andcombined organic extracts were washed with brine (50 mL), dried oversodium sulfate, filtered and concentrated in vacuo to get the crude.Trituration with diethyl ether (100 mL) led to methyl4-(tert-butylamino)-3-nitrobenzoate (Int-1, 1.2 g, 38.10%) as a yellowsolid. MS: m/z=253.1 [M+H]⁺.

Step-2: Synthesis of methyl 3-amino-4-(tert-butylamino)benzoate (Int-2):To a stirred solution of Int-1 (1.2 g, 4.70 mmol, 1 eq) in EtOH/water(1:1, 50 mL), Iron powder (1.33 g, 23.8 mmol, 5 eq), NH₄Cl (1.27 g, 23.8mmol, 5 eq) were added at room temperature. The resultant reactionmixture was heated to 100° C. for 16 h. The reaction was monitored byLCMS/TLC and after completion of the reaction, the mixture was filteredthrough a celite bed and washed with EtOAc (1×30 mL). Volatiles wereevaporated, quenched with sat. NaHCO₃ (20 mL), extracted with EtOAc(3×30 mL); the combined organic extracts were washed with brine (30 mL),dried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 50% EtOAc/heptane to obtain methyl3-amino-4-(tert-butylamino)benzoate (Int-2, 1.0 g, 95.07%) as a gummyliquid. MS: m/z=223.1 [M+H]⁺.

Step-3: Synthesis of methyl1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylate (Int-3): To a stirredsolution of Int-2 (1 g, 4.23 mmol, 1 eq) and triethyl orthoformate (3.1g, 21.18 mmol, 5 eq) in 1, 4-Dioxane (80 mL) PTSA (145 mg, 0.84 mmol,0.2 eq) was added at room temperature. The resulting reaction mixturewas heated to 100° C. for 16 h until consumption of SM by crudeLCMS/TLC. Volatiles were evaporated, washed with sat. NaHCO₃ (50 mL) andextracted with EtOAc (3×30 mL); combined organic extracts were washedwith brine (50 mL), dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 50% EtOAc/heptane to obtained methyl1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylate (Int-3, 600 mg, 61.1%yield, MS: m/z=233.1 [M+H]⁺) as a pale brown solid.

Step-4: Synthesis of 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylicacid (Int-4): Int-3 (600 mg, 2.43 mmol, 1 eq) in THF/water (8:2, 20 mL)was subjected to the general procedure for ester hydrolysis with NaOH toafford 1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-4, 320mg, 60.2%, MS: m/z=219.2 [M+H]⁺) as a pale brown sticky solid.

Step-5: Synthesis of(1-(tert-butyl)-1H-benzo[d]imidazol-5-yl)(4-fluoropiperidin-1-yl)methanone(MF-DH-203): A stirred solution of1-(tert-butyl)-1H-benzo[d]imidazole-5-carboxylic acid (320 mg, 1.46mmol, 1 eq) in DMF (10 v) was subjected to the general procedure foramide coupling using HATU to afford MF-DH-203 (20.4% yield) as an offwhite solid.

Synthesis of (4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl)indolin-5-yl)methanone MF-DH-165

Provided below is an exemplary scheme to synthesize(4-fluoropiperidin-1-yl)(1-(pyrazin-2-yl) indolin-5-yl)methanone,MF-DH-165, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 34

Step-1: Synthesis of methyl indoline-5-carboxylate (Int-1): To a stirredsolution of SM (2 g, 11.42 mmol, 1 eq) in acetic acid (20 mL), NaCNBH₃(2.15 g, 34.27 mmol, 3 eq) was added at 0° C. over 15 min. The resultingreaction mixture was stirred at room temperature for 12 h. Volatileswere evaporated, neutralized with NaHCO₃ to pH=7. The mixture wasextracted with EtOAc (2×20 mL). The combined organic extracts werewashed with brine (10 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography to afford methylindoline-5-carboxylate, Int-1 (1.65 g, 81.6%), as a brown solid. LCMS:97.65%, m/z=178.2 [M+H]⁺.

Step-2: Synthesis of methyl 1-(pyrazin-2-yl) indoline-5-carboxylate(Int-2): Using the general procedure for Buchwald coupling, methylindoline-5-carboxylate (Int-1) (500 mg, 2.83 mmol, 1 eq) and 2-chloropyrazine (355 mg, 3.10 mmol, 1.2 eq) were converted to Int-2 (310 mg,42.9%). LCMS: 95.10%, m/z=257.1[M+H]⁺.

Step-3: Synthesis of 1-(pyrazin-2-yl) indoline-5-carboxylic acid(Int-3): Methyl 1-(pyrazin-2-yl) indoline-5-carboxylate (110 mg, 0.43mmol, 1 eq) in MeOH/water (8:2, 10 mL) was subjected to the generalprocedure for ester hydrolysis with NaOH to afford 1-(pyrazin-2-yl)indoline-5-carboxylic acid (80 mg, 77.2%) as a pale brown sticky solid.MS: m/z=242.2[M+H]⁺.

Step-4: Synthesis of ((4-fluoropiperidin-1-yl(1-(pyrazin-2-yl)indolin-5-yl)methanone (MF-DH-165) (General procedure for amide couplingwith EDCI): To a stirred solution of 1-(pyrazin-2-yl)indoline-5-carboxylic acid (80 mg, 0.32 mmol, 1 eq) in DCM (10 v) underinert atmosphere were added EDCI (92 mg, 0.48 mmol, 1.5 eq) and HOBt (52mg, 0.38 mmol, 1.2 eq). The mixture was cooled to 0° C. and 4-fluoropiperidine (44 mg, 0.32 mmol, 1.0 eq) was added. To this stirredsolution N, N′-diisopropylethylamine (0.13 mL, 0.96 mmol, 3 eq), DMAP (5mg) was added at 0° C. and then the mixture was warmed and stirred atroom temperature for 16 h. The reaction mixture was quenched with icewater (10 mL) and extracted with EtOAc (2×15 mL). The combined organicextracts were washed with ice water (2×10 mL) and brine (10 mL), driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyfollowed by prep-HPLC to afford MF-DH-165 (7.2% yield) as an off whitesolid.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

Step-1: Synthesis of Int-1a (X=H) and Int-1b (X=F): The synthesis ofInt-1a and Int-1b is described in Schemes 9 and 10.

Step-2: General procedure for Ullmann reaction: synthesis of MF-DH-239,285, 294, 295, 296, 297, 298, 300, 302, 305, 306, 309, 310, 317, 321,322 and MF-DH-336: Int-1a and Int-1b were subjected to the generalprocedure for Ullmann coupling with the appropriate aryl bromides. Thecrude products were purified by flash chromatography to affordMF-DH-285, MF-DH-294, MF-DH-295, MF-DH-296, MF-DH-297, MF-DH-298,MF-DH-300, MF-DH-302, MF-DH-305, MF-DH-306, MF-DH-309, MF-DH-310,MF-DH-317, MF-DH-321, MF-DH-322 and MF-DH-336.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with N-ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with N-Aryl variations that areinhibitors of hydroxyprostaglandin dehydrogenase.

General procedure for the Oxidation of Nitriles (MF-DH-299 andMF-DH-301)

To a stirred solution of Int-2 (0.5 mmol, 1 eq) in DMSO (10 mL), K₂CO₃(2.0 eq), H₂O₂ (2 eq) was added at room temperature under aerobicconditions. Reaction mixture was heated to 80° C. for 16 h. The reactionwas monitored by LCMS/TLC and, after completion of the reaction,quenched with ice water (20 mL), filtered through Celite® bed, andwashed with EtOAc (20 ml). The organic phase was separated and theaqueous phase was extracted with ethyl acetate (2×10 mL). The combinedorganic extracts were washed with brine (20 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to obtain thecrude product, which was further purified by flash chromatography toafford MF-DH-299 and MF-DH-301.

General Procedure for Reduction of Nitriles (MF-DH-303 and MF-DH-304)

To a stirred solution of nitrile Int-2 (0.5 mmol, 1 eq) in MeOH (15 mL),Ra-Ni (20 mol %) was added at room temperature under nitrogenatmosphere. The reaction mixture was stirred for 16 h under hydrogenballoon atmosphere. The reaction was monitored by LCMS/TLC; uponcompletion of the reaction, the solids were filtered through a Celite®bed, washed with EtOAc (20 mL), and the volatiles were evaporated. Theaqueous phase was extracted with ethyl acetate (2×10 mL) and thecombined organic extracts were washed with a brine solution (20 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford the crude product, which was further purified byflash chromatography to afford MF-DH-303 and MF-DH-304.

General Procedure for Reduction of Aldehydes (MF-DH-307 and MF-DH-308)

To a stirred solution of aldehyde Int-2 (0.5 mmol, 1 eq) in MeOH (15mL), NaBH₄ (5 eq) was added portion wise at 0° C. for 15 min. Thereaction mixture was stirred for 6 h at room temperature. The reactionwas monitored by LCMS/TLC; upon completion, the reaction mixture wasquenched with satd. NH₄Cl (20 mL) and the volatiles were evaporated. Theaqueous phase was extracted with ethyl acetate (2×20 mL) and thecombined organic extracts were washed with brine solution (20 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto afford the crude product, which was further purified by flashchromatography afforded MF-DH-307 and MF-DH-308.

Synthesis of 3-chloro-pyrrolopyridine-5-carboxyamide Analogs withAmide/Aryl/Heteroaryl Variation

Provided below is an exemplary scheme to synthesize3-chloro-pyralopyridine-5-carboxyamide analogs withamide/aryl/heteroaryl variations that are inhibitors ofhydroxyprostaglandin dehydrogenase.

The synthesis of Int-1a (X=H) is described in Scheme 9. The synthesis ofInt-1b (X=F) is described in Scheme 31.

Step-1: Synthesis of MF-DH-191, MF-DH-250, MF-DH-251, MF-DH-273,MF-DH-274 and MF-DH-273: Int-1 was converted to the title compoundsaccording to the general procedure for Ullmann coupling with theappropriate aryl bromides.

Synthesis of MF-DH-146

Provided below is an exemplary scheme to synthesize MF-DH-146, which isan inhibitor of hydroxyprostaglandin dehydrogenase.

Step-1: SM 4-Chloro1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid wasconverted to Int-1 using the general procedure for HATU coupling toafford Int-1 (70%) as a brown solid. MS: m/z=282.2 [M+H]⁺.

Step-2: Int-2 was converted to MF-DH-146 using the general procedure forBuchwald coupling to afford MF-DH-146 as an off-white solid.

Synthesis of MF-DH-147

Provided below is an exemplary scheme to synthesize MF-DH-147, which isan inhibitor of hydroxyprostaglandin dehydrogenase.

Step-1: SM was converted to Int-1 using the general procedure forchlorination with NCS to afford Int-1 (334 mg; Yield: 70.1%) as a lightyellow solid. MS: m/z=231.10 [M+H]⁺.

Step-2: Int-1 was converted to Int-2 using the general procedure forHATU coupling to afford Int-2 (323 mg, 76%) as a brown solid. MS:m/z=299.2 [M+2H]⁺.

Step-3: Int-2 was converted to MF-DH-147 using the general procedure forBuchwald coupling to afford MF-DH-147 as an off-white solid.

Synthesis of MF-DH-148

Provided below is an exemplary scheme to synthesize MF-DH-148, which isan inhibitor of hydroxyprostaglandin dehydrogenase.

Step-1: SM 6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid wasconverted to Int-1 using the general procedure for HATU coupling toafford Int-1 (60%) as a brown liquid. MS: m/z=262.1 [M+H]⁺.

Step-2: Synthesis of MF-DH-148: Int-1 (0.95 mmol, 1 eq) and2-bromopyrazine (183 mg, 1.14 mmol, 1.2 eq) were reacted using thegeneral procedure for Buchwald coupling to afford the crude product,which was purified through silica gel column chromatography using 70%EtOAc/heptanes followed by Prep-HPLC purification to afford MF-DH-148.

Synthesis of MF-DH-149

Provided below is an exemplary scheme to synthesize MF-DH-149, which isan inhibitor of hydroxyprostaglandin dehydrogenase.

Step-1: 6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (SM) wasconverted to Int-1 using the general procedure for chlorination with NCSto afford Int-1 (300 mg; Yield: 84.2%) as a gummy liquid. MS: m/z=211.2[M+H]⁺, 212.2 [M+2H]⁺.

Step-2: Int-1 was converted to Int-2 using the general procedure forHATU coupling to afford Int-2 (259 mg/168 mg, 63%) as a brown liquid.MS: m/z=278.1 [M+H]⁺.

Step-3: Synthesis of MF-DH-149: Int-2 (0.95 mmol, 1 eq) and2-bromopyrazine were reacted using the general procedure for Buchwaldcoupling to afford the crude product, which was purified through silicagel column chromatography using 70% EtOAc/heptanes followed by Prep-HPLCpurification to afford MF-DH-149.

Synthesis of(1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-311) andpiperidin-1-yl(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-312)

Provided below is an exemplary scheme to synthesize(1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone,MF-DH-311, andpiperidin-1-yl(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone,MF-DH-312, which are inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1 is described in Scheme 9.

Step-1: Synthesis of MF-DH-311 and MF-DH-312: Sodium hydride (60% inmineral oil) (100 mg, 1.5 mmol, 1.52 eq) was added to a stirred solutionof piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (230 mg, 1mmol) in DMF (15 mL) at 0° C. and the resulting suspension was warmed toroom temperature and stirred for 1 h. Difluorocyclohexyl4-methylbenzenesulfonate, tosyl chloride, and mesyl chloride (1.2 eqeach) were added and the resulting reaction mixture was stirred for 6 h.The reaction was monitored by crude LCMS/TLC; after complete consumptionof the starting material, the reaction mixture was quenched with sat.NH₄Cl (10 ml) and extracted with EtOAc (2×50 mL). The combined organicextracts were washed with brine (20 mL), dried over sodium sulfate,filtered, and concentrated in vacuo to obtain the crude product. Thecrude product was purified through silica gel column chromatographyusing 60% EtOAc/heptane to afford(1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-311) andpiperidin-1-yl(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-312) as off-white solids.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesize MF-DH-318,MF-DH-320, MF-DH-322, MF-DH-342, MF-DH-344, MF-DH-346, MF-DH-366,MF-DH-389, and MF-DH-397, which are inhibitors of hydroxyprostaglandindehydrogenase.

Step-1: Synthesis of Int-1a (X=H) and Int-1b (X=F): The synthesis ofInt-1a and Int-1b is described in Scheme 9.

Int-1a was converted to MF-DH-318 using the general procedure forUllmann coupling using 7-bromoimidazo[1,2-a]pyridine to afford MF-DH-318as a sticky solid.

Int-1a was converted to MF-DH-320 using the general procedure forUllmann coupling using 3-bromo-5-methyl pyridine with Int-1 to affordMF-DH-320 as an off-white solid.

Int-1a was converted to MF-DH-322 using the general procedure forUllmann coupling using 5-bromopyridin-3-amine to afford MF-DH-322 as anoff-white solid.

Int-1b was converted to MF-DH-342 using the general procedure forUllmann coupling using 4-bromobenzo nitrile to afford MF-DH-342 as anoff-white solid.

Int-1 b was converted to MF-DH-344 using the general procedure forUllmann coupling using 3-bromobenzo nitrile to afford MF-DH-344 as anoff-white solid.

Int-1b was converted to MF-DH-346 using the general procedure forUllmann coupling using 4-bromo-N,N-dimethylaniline to afford MF-DH-346as an off-white solid.

Int-1a was converted to MF-DH-366 using the general procedure forUllmann coupling using 5-bromo-N,N-dimethylpyridin-2-amine to affordMF-DH-346 as an off-white solid.

Int-1a was converted to MF-DH-389 using the general procedure forUllmann coupling using 5-bromopicolinonitrile to afford MF-DH-389 as anoff-white solid.

Int-1a was converted to MF-DH-397 using the general procedure forUllmann coupling using 5-bromopyrimidine-2-carbonitrile to affordMF-DH-397 as an off-white solid.

Synthesis of(1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-319)

Provided below is an exemplary scheme to synthesize(1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone,MF-DH-319, that is an inhibitor of hydroxyprostaglandin dehydrogenase.

Scheme 44

Step-A: Synthesis of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (Int-A) and5-bromo-1-(4-methoxybenzyl)-2H-indazole (Int-A′): To a stirred solutionof 6-bromoindazole (1 g, 5.07 mmol, 1 eq) in DMF (15 mL), NaH (60% inmineral oil)(0.24 g, 6.08 mmol, 1.2 eq) was added at 0° C. to roomtemperature for 1 h. To this stirred suspension of PMBCl (1.18 g, 7.60mmol, 1.5 eq) was added and then the resulting reaction mixture wasstirred for 4 h. The reaction was monitored by crude LCMS/TLC; aftercomplete consumption of the starting material, the reaction mixture wasquenched with sat. NH₄Cl (10 ml) and extracted with EtOAc (2×50 mL).Combined organic extracts were washed with brine (20 mL), dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using40% EtOAc/heptane to afford 5-bromo-1-(4-methoxybenzyl)-1H-indazole,Int-A (0.81 g, 50.06%) and 5-bromo-1-(4-methoxybenzyl)-2H-indazole,Int-A′ (0.55 g, 34.3%) as off-white solids. LCMS: 98.3%,m/z=318.1[M+2H]⁻.

Step-1: The synthesis of Int-1 is described in Scheme 9. Int-1 wasconverted to MF-DH-337 using the general procedure for Ullmann couplingusing 5-bromo-1-(4-methoxybenzyl)-1H-indazole (Int-A) with Int-1 toafford MF-DH-337 as sticky solid.

Step-3: Int-1 was converted to MF-DH-340 using the general procedure forUllmann coupling using 5-bromo-1-(4-methoxybenzyl)-2H-indazole (Int-A′)with Int-1 to afford MF-DH-340 as an off-white solid.

Step-2: Synthesis of 5(1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-319): To a stirred solution of MF-DH-337 (120 mg, 0.257 mmol, 1eq) in DCE (15 mL), TFA (4 mL) was added at 0° C. and stirred at roomtemperature for 1 h and then heated to 80° C. for 16 h. The reaction wasmonitored by crude LCMS/TLC; after complete consumption of the startingmaterial, the reaction mixture was quenched with satd. NaHCO₃ (10 ml)and extracted with EtOAc (2×50 mL). Combined organic extracts werewashed with brine (20 mL); dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 40% EtOAc/heptane toafford 5(1-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-319) as a sticky liquid.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1a (X, X′=H) and Int-1b (X=H, X′=F) is described inScheme 9.

Synthesis of Int-1c (X, X′=F): To a stirred solution of11H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (30 g, 185.1 mmol, 1 eq) inDMF (5 v) under inert atmosphere were added HATU (84.44 g, 222.2 mmol,1.3 eq) and 4,4-difluoropiperidine (31.98 g, 203.7 mmol, 1.1 eq) wasadded at 0° C. To this stirred solution N, N′-diisopropylethylamine(119.6 g, 925.9 mmol, 5 eq) was added at 0° C. and then continued forstirring at RT for 16 h. The reaction mixture was quenched with icewater (200 mL), extracted with EtOAc (3×200 mL). The combined organicextracts were washed with ice water (2×100 mL) and brine (100 mL); driedover sodium sulphate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through flash column chromatography toafford 32.5 g of Int-1c (66.2% yield). ¹HNMR (400 MHz, DMSO-d6): δ 11.89(s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.56 (t, J=2.8Hz, 1H), 6.52 (dd, J=1.6, 3.2 Hz, 1H), 3.64-3.58 (m, 4H), 2.09-2.01 (m,4H). LCMS: 97.17%; MS: 266 [M+H]⁺.

Step-1: Int-1a, Int-1b, and Int-1c were converted to Int-2a:(Ar₁=Pyridine-2-CN; X, X′=H) 30% yield, MS: m/z=332.2[M+H]⁺; Int-2b:(Ar₁=Pyrazine-2-CN; X, X′=H) 68% yield, MS: m/z=333.2 [M+H]⁺; Int-2c:(Ar₁=4-CHO-Ph; X, X′=H) 83% yield, MS: m/z=334.1 [M+H]⁺; Int-2d:(Ar₁=3-CHO-Ph; X, X′=H) 53% yield, MS: m/z=334.1 [M+H]⁺, Int-2e:(Ar₁=4-CH₃C═O-Ph; X, X′=H) 62% yield, MS: m/z=348.1 [M+H]⁺; Int-2f:(Ar₁=3-CH₃C═O-Ph; X, X′=H) 60% yield, MS: m/z=348.1 [M+H]⁺, Int-2g:(Ar₁=4-CHO-Ph; X=H, X′=F) 58% yield, MS: m/z=353.1 [M+H]⁺; Int-2 h:(Ar₁=3-CHO-Ph, X=H, X′=F) 78% yield, MS: m/z=353.1 [M+H]⁺, and Int-2i:(Ar₁=4-CN-Ph, X=H, X′=F) 43% yield, MS: m/z=349.2 [M+H]⁺.

Step 2: Using the general procedure for the oxidation of nitriles,MF-DH-342 (synthesis described in Scheme 43), MF-DH-344 (synthesisdescribed in Scheme 43), Int-2a, Int-2b, and Int-21 were converted toMF-DH-343, MF-DH-345, MF-DH-365, MF-DH-384, and MF-DH-394, which wereisolated as off-white solids.

Using the general procedure for reduction of aldehydes/ketones,MF-DH-347, MF-DH-348, MF-DH-347, and MF-DH-348 were obtained as stickyliquids.

General Procedure for Aldehyde/Ketone Alkylation

To a stirred solution of aldehyde/ketone Int-2c, Int-2e, Int-2d, andInt-2f (0.5 mmol, 1 eq) in THF (15 mL), MeMgBr (2M in THF, 2 eq) wasadded portion wise at 0° C. for 15 min. The reaction mixture was stirredfor 5 h at room temperatures. The reaction was monitored by LCMS/TLC.Upon completion, the reaction mixture was quenched with satd. NH₄Cl (20mL), extracted with EtOAc (2×20 mL), and the combined organic extractswere washed with brine solution (20 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to afford the crudeproduct, which was further purified by flash chromatography to affordMF-DH-370, MF-DH-374, MF-DH-371, and MF-DH-375 as off-white solids andsticky liquids.

General Procedure for Aldehyde Reduction: To a stirred solution ofaldehyde/ketone Int-2g/Int-2 h (0.5 mmol, 1 eq) in MeOH (15 mL), NaBH₄(4 eq.) was added portion wise at 0° C. for 15 min. The reaction mixturewas stirred for 2 h at room temperature. Upon completion, the reactionmixture was concentrated under vacuum, diluted with water, and extractedwith EtOAc (2×20 mL). The combined organic extracts were washed withbrine solution (20 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to afford the crude product, whichwas further purified by flash chromatography to afford MF-DH-347 andMF-DH-348 as off white solids.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation (MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327, MF-DH-328,MF-DH-329)

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

Step-1: Synthesis of methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate(Int-1): To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (5 g, 30.08 mmol, 1 eq) in DCM (100 mL) were added oxalylchloride(5.3 mL, 61.60 mmol, 2 eq) followed by DMF (0.5 mL) at 0° C. for 30 minand then was stirred at room temperature for 1 h. The reaction wasmonitored by TLC, after completion of the reaction, quenched withmethanol (20 mL), and stirred at room temperature for 12 h. Then solventwas evaporated under reduced pressure and diluted with ethyl acetate(100 mL), washed with sat. NaHCO₃ solution (50 mL), and brine (50 mL)and the organic phases were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to obtain methyl1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-1 (5.38 g, 99%) as anoff-white solid. LCMS: 96.42%, m/z=177.1[M+H]⁺. ¹H NMR (DMSO-d6, 400MHz): δ 12.08 (br s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.56 (s, 1H), 6.57(s, 1H), 3.81 (s, 3H).

Step-2 Synthesis of methyl1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Int-2):Using the general procedure for Ullmann reaction Int-1 (2.5 g, 14.1mmol) was converted to Int-2 (2.51 g, 62.5%) which was isolated as anoff-white solid. LCMS: 99.12%, m/z=283.1[M+H]⁺.

Step-3: Synthesis of1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-3):Methyl 1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.5g, 8 mmol, 1 eq) in MeOH:water (8:2, 30 mL) was subjected to the generalprocedure for ester hydrolysis with NaOH to afford Int-3 (1.5 g, 65.21%)as a pale brown sticky solid. LCMS: 96.35 m/z=269.1[M+H]⁺.

Step-4: Synthesis of MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327,MF-DH-328, and MF-DH-329: Using the general procedure for HATU coupling,Int-3 was converted to MF-DH-MF-DH-324, MF-DH-325, MF-DH-326, MF-DH-327,MF-DH-328, and MF-DH-329 which were isolated after purification as offwhite solid/sticky solids.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1a (X=H) and Int-1b (X=F) is described in Scheme 9.

Step-1: Int-1a/1b was converted to Int-2a/2b using the general procedurefor Ullmann coupling with 4-bromobenzoate to afford Int-2a (X=H, 55%yield, MS: m/z=364.1 [M+1]⁺) and Int-2b (X=F, 60.74% yield, MS:m/z=382.1 [M+1]⁺) as off-white solids.

Step-2: Int-2 was converted to Int-3a (X=H, 86% yield, m/z=350.1 [M+1]⁺)and Int-3b (X=F, 89% yield, MS: m/z=366.1 [M−H]⁻) using the generalprocedure for ester hydrolysis with NaOH. The crudes were taken to thenext stage without purification.

Step-3: Int-3 was subjected to the general procedure for amide couplingswith HATU to afford MF-DH-357, MF-DH-367, MF-DH-358, MF-DH-368,MF-DH-359, and MF-DH-360.

Synthesis of Azabenzimidazole Analogs with Aryl/Amide Variation

Provided below is an exemplary scheme to synthesize azabenzimidazoleanalogs with amide/Aryl variations that are inhibitors ofhydroxyprostaglandin dehydrogenase.

Step-1: Synthesis of Int-1 general procedure: In a sealed bomb, methyl6-chloro-5-nitronicotinate (7 g, 32.31 mmol, 1 eq), Arylamines (Ar—NH₂,1 eq) were dissolved in EtOH (70 mL). To this stirring solution K₂CO₃ (1eq) was added at room temperature. Steel bomb cap was tightly closedthen resultant reaction mixture was heated to 100° C. for 16 h. Thereaction was monitored by crude LCMS/TLC; after completion of thereaction; cooled to room temperature and then filtered, washed withEtOAc (50 mL). Volatiles were evaporated, quenched with satd. NH₄Cl (100mL), extracted with EtOAc (3×50 mL) and combined organic extracts werewashed with brine (50 mL). Dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the yellow solid, trituration with DEE(100 mL) afforded Int-1a (Ar=3-Cl phenyl, 64% yield, MS: m/z=307.2[M+H]⁺); Int-1 b (Ar=4-OMePh, 87% yield, MS: m/z=318.2 [M+H]⁺); Int-1c(Ar=4-F-Ph, 70% yield, MS: [M+H]⁺); Int-1d (Ar=3,4 Di FluoroPh, 96%yield); Int-1e (Ar=4-OCF₃Ph, 96% yield, MS: m/z=328.2); Jot-1f(Ar=4-OCHF₂Ph, 66% yield, MS: m/z=338.2 [M+H]⁺); Int-1g (Ar=4-OEtPh, 62%yield, MS: m/z=317.2 [M+H]⁺); Int-1 h (Ar=3-OCF₃Ph, 72% yield, MS:m/z=326.2 [M+H]⁺); Int-1i (Ar=3-OCHF₂Ph, 62% yield, MS: m/z=309.2[M+H]⁺); Int-1j (Ar=3-pentyl, 83% yield, MS: m/z=254.1 [M+H]⁺); Int-1k(Ar=4-OHPh, 76% yield, MS: m/z=290.1 [M+H]⁺); and Int-1l (Ar=4-CNPh,crude, m/z=299.1 [M+H]⁺).

Step-2: Synthesis of Int-2: Int-1 (2 g, 1 eq) was subjected to thegeneral procedure for aryl nitro reduction using Fe. The crude waspurified through silica gel column chromatography using 60% to 70%EtOAc/heptane to afford Int-2a (Ar=3-ClPh, 20% yield, MS: m/z=291.0[M+H]⁺); Int-2b (Ar=4-OMePh, crude, MS: m/z=288.2 [M+H]⁺); Int-2c(Ar=4-FPh, crude, MS: m/z=261.2 [M+H]⁺); Int-2d (Ar=3,4-Di FluoroPh, 96%yield, MS: m/z=280.2 [M+H]⁺); Int-2e (Ar=4-OCF₃Ph, 96% yield, MS:m/z=328.2); Int-2f (Ar=4-OCHF₂Ph, 71.4% yield, MS: m/z=324.2 [M+1]⁺);Int-2g (Ar=4-OEtPh, 93% yield, MS: m/z=286.2 [M+H]⁺); Int-2 h(Ar=3-OCF₃Ph, 68% yield, MS: m/z=338.1 [M+H]⁺); Int-2i (Ar=3-OCHF₂Ph,57% yield, MS: m/z=310.2 [M+1H]⁺); Int-2j (Ar=3-pentyl, 84% yield, MS:m/z=252.1 [M+H]⁺); Int 2k (Ar=4-OHPh, 76% yield, MS: m/z=290.1 [M+H]⁺);and Int-2l (Ar=4-CNPh, crude, MS: m/z=269.2 [M+H]⁺).

Step-3: Synthesis of Int-3 general procedure: To a stirred solution ofInt-2 (1.5 g, 1 eq) and triethyl orthoformate (5 eq) in dioxane (20 mL),PTSA (0.2 eq) was added at room temperature. The resulting reactionmixture was heated to 100° C. for 16 h. The reaction was monitored bycrude LCMS/TLC; after complete consumption of the starting material, thereaction mixture was quenched with sat. NaHCO₃ solution (20 mL),extracted with EtOAc (3×50 mL); the combined organic extracts werewashed with brine (20 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purified bysilica gel column chromatography using 50% EtOAc/heptane to obtainInt-3a (Ar=3-ClPh, 20% yield, MS: m/z=291.0 [M+H]⁺); Int-3b (Ar=4-OMePh,58% yield, MS: m/z=298.2 [M+1]⁺), Int-3c (Ar=4-FPh, crude, MS: m/z=271.2[M+H]⁺); Int-3d (Ar=3,4-Di FluoroPh, crude, MS: m/z=290.1 [M+H]⁺);Int-3e (Ar=4-OCF₃Ph, 81% yield, MS: m/z=338.1); Int-3f (Ar=4-OCHF₂Ph,97.1% yield, MS: m/z=334.1 [M+H]⁺); Int-3g (Ar=4-OEtPh, 56% yield, MS:m/z=297.2 [M+H]⁺); Int-3 h (Ar=3-OCF₃Ph, 67% yield, MS: m/z=276.1[M+H]⁺); Int-3i (Ar=3-OCHF₂Ph, 65% yield, MS: m/z=309.2 [M+H]⁺); Int-3j(Ar=3-pentyl, 84% yield, MS: m/z=262.2 [M+H]⁺); Int 3k (Ar=4-OHPh, 58%yield, MS: m/z=269.2 [M+H]⁺); and Int-3l (Ar=4-CNPh, 56.6% yield, MS:m/z=279.1 [M+H]⁺).

Step-4: Synthesis of Int-4: Int-3 (1.2 g, 1 eq) in MeOH:water (1:1, 20mL) was subjected to the general procedure for ester hydrolysis withLiOH to afford Int-4a (Ar=3-ClPh, 82% yield, MS: m/z=291.0 [M+H]⁺);Int-4b (Ar=4-OMePh, 82% yield, MS: m/z=270.1 [M+H]⁺); Int-4c (Ar=4-FPh,19% yield), Int-4d (Ar=3,4 DiFluoroPh, 56% yield, MS: m/z=376.1 [M+H]⁺);Int-4e (Ar=4-OCF₃Ph, 90% yield, MS: m/z=324.1 [M+H]⁺); Int-4f(Ar=4-OCHF₂Ph, 43.4% yield, MS: m/z=306.1 [M+H]⁺); Int-4g (Ar=4-OEtPh,85.2% yield, MS: m/z=282.1 [M−H]⁻); Int-4 h (Ar=3-OCF₃Ph, 52.2% yield,MS: m/z=338.2 [M+H]⁺); Int-4i (Ar=3-OCHF₂Ph, 78% yield, MS: m/z=306.1[M+H]⁺), Int-4j (Ar=3-pentyl, 81% yield, MS: m/z=234.1[M+H]⁺); Int 4k(Ar=4-OHPh, 85% yield, MS: m/z=256.1 [M+H]⁺); and Int-4l (Ar=4-CNPh, 90%yield, MS: m/z=263.1 [M−H]⁻).

Step-5: Synthesis of MF-DH-214, MF-DH-215, MF-DH-216, MF-DH-217,MF-DH-218, MF-DH-219, MF-DH-222, MF-DH-223, MF-DH-224, MF-DH-225,MF-DH-226, MF-DH-227, MF-DH-228, MF-DH-229, MF-DH-236, MF-DH-238,MF-DH-442, MF-DH-138, and MF-DH-443: Int-4 (1 eq) andpiperidine/4-fluoropiperidine/4,4-difluoropiperidine/3-fluoroazetidine/3-chloroazetidine(1.2 eq) were subjected to the general procedure for amide coupling withHATU. The crudes were purified by flash silica gel column chromatographyusing 60% EtOAc:heptane or by Prep-HPLC purification to affordMF-DH-214, MF-DH-215, MF-DH-216, MF-DH-217, MF-DH-218, MF-DH-219,MF-DH-222, MF-DH-223, MF-DH-224, MF-DH-225, MF-DH-226, MF-DH-227,MF-DH-228, MF-DH-229, MF-DH-236, MF-DH-238, MF-DH-442, MF-DH-138, andMF-DH-443 as off-white solids/gummy liquids.

Synthesis of MF-DH-464: MF-DH-442 was subjected to the general procedurefor oxidation of nitriles. The crude was purified by flashchromatography to afford MF-DH-464 as an off-white solid.

Synthesis of MF-DH-176 and MF-DH-205

Scheme 49

The synthesis of Int-2 is described in Scheme 48.

Step-1: Synthesis of methyl3-(4-methoxyphenyl)-2-methyl-3H-Imidazo[4,5-b]pyridine-6-carboxylate(Int-3): To a stirred solution5-amino-6-((4-methoxyphenyl)amino)nicotinate (300 mg, 1.09 mmol, 1.0 eq)in DMF (2 mL) was added acetaldehyde (74 mg, 3.27 mmol, 3.0 eq) andsodium sulfate (3.09 mg, 2.18 mmol, 2.0 eq) at room temperature. Thereaction was heated to 80° C. for 12 h. The reaction was monitored bycrude LCMS/TLC; after complete consumption of the starting material, thereaction mixture was quenched with ice water (20 mL), extracted withEtOAc (2×15 mL). The combined organic extracts were washed with icewater (2×10 mL) and brine (10 mL), dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purified bysilica gel column chromatography using 50% EtOAc/Hexane to obtain methyl3-(4-methoxyphenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate(210 mg, 64.4%) as an off-white solid. MS: m/z=311.1 [M+H]⁺.

Step-2: Synthesis of3-(4-methoxyphenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid(Int-4) Using the general procedure for ester hydrolysis with LiOH,methyl3-(4-methoxyphenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate(Int-3)(210 mg) was convened to3-(4-methoxyphenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid(Int-4, 160 mg, 79.2%) which was isolated as an off-white solid MS:m/z=284.1 [M+H]⁺.

Step-3: Synthesis of MF-DH-176 and MF-DH-205:3-(4-methoxyphenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid(Int-4) was converted to MF-DH-176 and MF-DH-205 using the generalprocedure for amide coupling using HATU.

Synthesis of MF-DH-117 and MF-DH-130

The synthesis of Int-2 is described in Scheme 48.

Step-1: Synthesis of methyl5-(2-cyanoacetamido)-6-((4-methoxyphenyl)amino)nicotinate (Int-3): Usingthe general procedure for amide coupling with HATU, methyl5-amino-6-((4-methoxyphenyl)amino)nicotinate Int-2 (2 g) was convertedto methyl 5-(2-cyanoacetamido)-6-((4-methoxyphenyl)amino)nicotinate(Int-3) which was isolated as an off-white solid. MS: m/z=355.0 [M+H]⁺.

Step-2: Synthesis of methyl2-(cyanomethyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(Int-4): To a stirred solution of methyl5-(2-cyanoacetamido)-6-((4-methoxyphenyl)amino)nicotinate (Int-3) (2 g,5.89 mmol. 1.0 eq) in DCE (20 mL) at 00 C, was added trifluoroaceticacid (5 mL). The reaction mixture was slowly brought to room temperatureand heated to 80° C., for 16 h. The reaction was monitored by crudeLCMS/TLC; after complete consumption of the starting material, thereaction mixture was made neutral with saturated sodium bicarbonate (50mL) and extracted with EtOAc (2×50 mL). The combined organic extractswere washed with water (2×10 mL) and brine (10 mL), dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was used in the next step without further purification to obtainmethyl2-(cyanomethyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(Int-4) (1.8 g, 94% yield) as an off-white solid. MS: m/z=323.2 [M+H]⁺.

Step-3: Synthesis of2-(cyanomethyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (Int-5) Using the general procedure for ester hydrolysis with LiOH,methyl2-(cyanomethyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(Int-4) (700 mg) was converted to2-(cyanomethyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (Int-5) (320 mg, 47.2%) isolated as an off-white solid. MS:m/z=307.0 [M−H]⁻.

Step-4: Synthesis of MF-DH-117 and MF-DH-130: Using the generalprocedure for amide coupling with HATU,2-(cyanomethyl)-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (Int-5) (1 eq) was converted to MF-DH-130. The crude was purifiedby silica gel column chromatography using 2-3% MeOH:CH₂Cl₂ followed byPrep-HPLC purification to obtain MF-DH-130 as an off-white solid.

General procedure for reduction of nitriles and acetylation for thesynthesis of MF-DH-117: Step-5: To a stirred solution of MF-DH-130 (0.5mmol, 1 eq) in MeOH (15 mL), NiCl2·6H2O (1 eq %) followed by NaBH₄ (5eq) was added at 0° C. then warmed to room temperature for 30 min underhydrogen/nitrogen atmosphere. To this cooled reaction mixture, addedAc₂O (2 eq) and then the reaction mixture was stirred for 16 h. Thereaction was monitored by LCMS/TLC, after completion of the reaction,quenched with ice water (20 mL) filtered through celite bed andvolatiles were evaporated. The mixture was extracted with EtOAc (2×20ml), and combined organic extracts were washed with brine (20 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure toobtain the crude. This was further purified by flash chromatography toafford MF-DH-117 as an off-white solid.

Synthesis of MF-DH-184, MF-DH-185, MF-DH-195, MF-DH-267 and MF-DH-268

The synthesis of Int-2 is described in Scheme 48.

Step-1: Synthesis of Int-3, general procedure: To a stirred solution ofmethyl 5-amino-6-((4-methoxyphenyl)amino)nicotinate Int-2 in DMF (10 V)was added respective aldehydes (4.0 eq), sodium thiosulfate (1.0 eq) wasadded and then heated to 70-800 C for 16 h. The reaction was monitoredby crude LCMS/TLC; after complete consumption of the starting material,the reaction mixture was quenched with ice water (20 mL) and extractedwith EtOAc (2×30 mL). The combined organic extracts were washed withwater (2×10 mL) and brine (10 mL), dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude as a thick syrup. Thecrude was used in the next step without further purification.

Step-2: Synthesis of Int-4: Using the general procedure for esterhydrolysis with LiOH, Int-3 was converted to Int-4a (R=Methyl, 39%yield, MS: m/z=298.0 [M+H]⁺); Int-4b (R=Methoxy methyl, 65.2% yield, MS:m/z=326.0 [M−H]⁻); and Int-4c (R=trifluoroethyl, 77% yield, MS:m/z=366.1 [M+H]⁺), which were isolated as off-white solids.

Step-3: Synthesis of MF-DH-184, MF-DH-185, MF-DH-195, MF-DH-267 andMF-DH-268 general procedure: Using the general procedure for amidecoupling with HATU, Int-5 was converted to crude products. The crude waspurified through silica gel column chromatography using 2-3% MeOH:CH₂Cl₂followed by Prep-HPLC purification to obtain MF-DH-184, MF-DH-185,MF-DH-195, MF-DH-267 and MF-DH-268 as off-white solids/gummy liquids.

Synthesis of5-(5-(piperidine-1-carbonyl/4-fluoropiperidine-1-carbonyl/-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)carboxamide Analogs with Aryl/Amide Variation

Provided below is an exemplary scheme to synthesize5-(5-(piperidine-1-carbonyl/4-fluoropiperidine-1-carbonyl/-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)carboxamide analogs with aryl/amide variations that are inhibitors ofhydroxyprostaglandin dehydrogenase.

The synthesis of Int-1a (X, X′=H) is described in Scheme 9.

The synthesis of Int-1b (X, X′=F) is described in Scheme 45.

Step-1: Synthesis of MF-DH-364, MF-DH-392, MF-DH-393, MF-DH-397,MF-DH-396, MF-DH-439, MF-DH-440, MF-DH-441, MF-DH-495, MF-DH-496 andMF-DH-502: Using the general procedure for Ullmann coupling with thecorresponding aryl bromides, Int-1a and Int-1b were converted to thetitle compounds after the crude was purified by flash column/Prep-HPLCpurification.

Synthesis of(1-(4-(1-aminoethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone/(1-(3-(1-aminoethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-372 and MF-DH-376)

Step-1: General procedure for synthesis of1-(4/3-(5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)ethan-1-one/4/3-(5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzaldehyde(Int-2): Piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1)was converted to1-(3-(5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)ethan-1-one(Int-2a) and1-(4-(5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)ethan-1-one(Int-2b) using the general procedure for Ullmann coupling withrespective 3/4-bromobenzophenone to afford Int-2a (33% yield, MS:m/z=348.2 [M+H]⁺) and Int-2b (54% yield, MS: m/z=348.2 [M+H]⁺).

Step-2: General procedure for the synthesis of(1-(4/3-(2-hydroxypropan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-371 and MF-DH-375): To a stirred solution of ketone(Int-2a/Int-2b) (0.5 mmol, 1 eq) in THF (15 mL), methyl magnesiumbromide (1.5 eq) was added at 0° C. under nitrogen atmosphere and thenstirred for 4 h at room temperature. The reaction was monitored byLCMS/TLC, after completion of the reaction, quenched with satd. NH₄Cl(15 ml); the aqueous phase was extracted with ethyl acetate (2×10 mL)and combined organic extracts were washed with brine (20 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure toobtain the crude. This was further purified by flash chromatography toafford MF-DH-371 and MF-DH-375 as an off-white solid/sticky liquid.

Step-2: Synthesis of (1-(3/4-(1-aminoethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-372 and MF-DH-376): To a stirred solution of Int-2a/Int-2b inmethanol (10 vol), ammonium acetate (5.0 eq) was added at roomtemperature. The reaction was heated to 50° C., for 5 h. The reactionmixture was cooled to 0° C., sodium cyanoborohydride (3.0 eq) was addedand stirred at room temperature for 16 h. The reaction was monitored byTLC, after completion of the reaction, the reaction mixture was dilutedwith water and extracted with DCM. The organic phases were dried oversodium sulfate, filtered and concentrated under reduced pressure toafford the crude. This was further purified by Prep-HPLC to affordMF-DH-372 and MF-DH-376 as sticky liquids.

Synthesis of2-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)aceticacid/1-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)cyclopropane-1-carboxylicacid/4-(5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (MF-DH-426, 427 and MF-DH-433)

The synthesis of Int-1a (X, X′=F) is described in Scheme 45. Thesynthesis of Int-1b (X, X′=H) is described in Scheme 9.

Step-1: Synthesis of methyl2-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acetate/methyl1-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)cyclopropane-1-carboxylate/(methyl4-(5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl) (Int-2):(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone/piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) was converted to Int-2a (64.2% yield, MS: m/z=414.2 [M+H]⁺);Int-2b (60.4% yield, MS: m/z=440.2 [M+H]⁺); and Int-2c (80% yield, MS:m/z=364.2 [M+H]⁺) using the general procedure for Ullmann coupling.

Step-2: General procedure for synthesis of2-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)aceticacid/1-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenylcyclopropane-1-carboxylicacid/4-(5-(piperidine-1-carbonyl)-H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (W-DH-426,427 and MF-DH-433): Int-2a, Int-2b, and Int-2c wereconverted to MF-DH-426, MF-DH-427 and MF-DH-433 using the generalprocedure for ester hydrolysis with NOH.

Synthesis of pyrrolopyridine-4,4-difluoropiperidine-5-carboxyamideanalogs with 4-benzamide Variation (MF-DH-404, 412, 413, 418, 421, 451,431, 411, 409, 403, 419, 420, 428, 429, 432 and MF-DH-450)

Provided below is an exemplary scheme to synthesizepyrrolopyridine-4,4-difluoropiperidine-5-carboxyamide analogs with4-benzamide variations that are inhibitors of hydroxyprostaglandindehydrogenase.

Scheme 55

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of methyl4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (3g, 11.3 mmol, 1.0 eq) was converted to methyl4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2) using the general procedure for Ullmann coupling to afford 3.05g (65%) of the product as an off-white solid. MS: 399.1 (M+1).

Step-2: synthesis of4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (Int-3): methyl4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(3.0 g, 7.5 mmol) was converted to4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid using the general procedure for ester hydrolysis with LiOH. Int-3(MF-DH-424) was isolated as an off-white solid (1.64 g, Yield 57%.),LCMS 386.1 [M+H]⁺; HPLC purity 99.34%.

Step-3: Synthesis of4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(methylsulfonyl)benzamide(MF-DH-428):4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (Int-3) was converted to4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(methylsulfonyl)benzamide(MF-DH-428) using the general procedure for amide coupling with EDCI(1.5 eq), DMAP (1 eq).4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(methylsulfonyl)benzamidewas isolated as an off white solid.

Step-3 and 4: Synthesis of MF-DH-411, MF-DH-419 and MF-DH-420:4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (Int-3) was converted to MF-DH-404, MF-DH-412, MF-DH-413,MF-DH-418, MF-DH-421, MF-DH-451 and the N-Boc amides of MF-DH-411, 419and MF-DH-420 using the general procedure for amide coupling with HATUand the respective amines. Subsequent deprotection of the Boc-protectedamines with 4M dioxane HCl/TFA followed by neutralization with NaHCO₃and a normal extractive work-up afforded MF-DH-411, MF-DH-419, andMF-DH-420) as off-white solids/gummy liquids.

Step-5: Synthesis of4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-(methylsulfonamido)ethyl)benzamide(MF-DH-409):N-(2-aminoethyl)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-411) was converted to MF-DH-409 using NaH (1 eq) methane sulfonylchloride (1.3 eq) in DMF (5V) followed by a normal extractive workup andpurification to afford the final compound as an off white solid.

Step-3 and 6: Synthesis of MF-DH-429, MF-DH-431, and MF-DH-432: Int-3was converted to methyl esters of MF-DH-429, MF-DH-431, and MF-DH-432using the general procedure for amide coupling with HATU an L-Prolinemethyl ester/methyl1-aminocyclopropane-1-carboxylate/3-amino-3-methylbutanoic acid (1 eq)followed by hydrolysis under general procedure of ester hydrolysis withLiOH to afford final compounds MF-DH-429, MF-DH-431, and MF-DH-432 asoff white solids/gummy liquids.

Step-7: Synthesis of4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-pivalamidoethyl)benzamide(MF-DH-403):N-(2-aminoethyl)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamidewas converted to4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-pivalamidoethyl)benzamide(MF-DH-403) using the general procedure for amide coupling with HATU.This afforded the final compound as an off white solid.

Step-8: Synthesis of(S)-1-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)pyrrolidine-2-carboxamide(MF-DH-450): MF-DH-432 was converted to(S)-1-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)pyrrolidine-2-carboxamide(MF-DH-450) using general procedure for amide coupling with HATU andNH₄Cl to afford MF-DH-450 as an off white solid.

Synthesis of Pyrrolopyridine-4,4-difluoropiperidine-5-carboxyamideAnalogs with 3-benzamide Variation (MF-DH-467, MF-DH-468, MF-DH-480,MF-DH-486, MF-DH-489, MF-DH-498, and MF-DH-499)

Provided below is an exemplary scheme to synthesizePyrrolopyridine-4,4-difluoropiperidine-5-carboxyamide analogs with3-benzamide variations that are inhibitors of hydroxyprostaglandindehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of methyl3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (2g, 7.48 mmol, 1.0 eq) was converted to methyl3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2) using the general procedure for Ullmann coupling with methyl3-bromo benzoate (2.412 g, 1.5 eq) to afford 1.77 g (59%) of product asan off-white solid. LCMS 399.1 (M+1).

Step-2: Synthesis of3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (Int-3): methyl3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(1.75 g, 4.39 mmol) was converted to3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid using the general procedure forester hydrolysis with LiOH.MF-DH-507 (Int-3) was isolated as an off-white solid (0.87 g, Yield52%.), LCMS 386.1 (M+1); HPLC purity 97.07%.

Step-3: Synthesis of3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-hydroxyethyl)benzamide(MF-DH-468)/(3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)-L-proline(MF-DH-489)/N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-498)/N-(1-cyclopropyl-1H-pyrazol-3-yl)-3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-499):4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid was converted to3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-hydroxyethyl)benzamide/(3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)-L-proline/N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide/N-(1-cyclopropyl-1H-pyrazol-3-yl)-3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide using general procedure for amide coupling with HATU.

Step-3 and 4: Synthesis ofN-(2-aminoethyl)-3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide:3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (Int-3) was converted to tert-butyl(2-(3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamido)ethyl)carbamate(54.94% yield, MS: m/z=528.2 [M+H]⁺) using the general procedure foramide coupling with HATU with N-Boc diaminoethane. tert-butyl(2-(3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamido)ethyl)carbamatewas subjected to deprotection with 4M HCl in dioxane. Organics wereneutralized with satd. NaHCO₃ solution and worked up to affordN-(2-aminoethyl)-3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (MF-DH-467) as an off white solid.

Step-5: Synthesis of3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-(methylsulfonamido)ethyl)benzamide(MF-DH-480):N-(2-aminoethyl)-3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-467) was converted to MF-DH-480 using NaH (1 eq) methane sulfonylchloride (1.3 eq) in DMF (5V). An extractive workup and purificationafforded the final compound as an off white solid.

Step-3: Synthesis of(S)-1-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)pyrrolidine-2-carboxamide(MF-DH-486):(3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)-L-proline(MF-DH-489) was converted to(S)-1-(3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)pyrrolidine-2-carboxamide(MF-DH-486) using general procedure for amide coupling with HATU andNH₄Cl to afford(S)-1-(4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoyl)pyrrolidine-2-carboxamideas an off white solid.

Step-3 and 6:(4,4-difluoropiperidin-1-yl)(1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneand(4,4-difluoropiperidin-1-yl)(1-(3-(1-oxidothiazolidine-3-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-497) and (MF-DH-527):3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (Int-3) was converted to(4,4-difluoropiperidin-1-yl)(1-(3-(thiazolidine-3-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneusing general procedure for amide coupling with HATU. The resultingproduct,(4,4-difluoropiperidin-1-yl)(1-(3-(thiazolidine-3-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(95.13% yield, MS: m/z=457.3 [M+1]⁺), was oxidized with m-CPBA (1.5 eq)purified via prep-HPLC to afford(4,4-difluoropiperidin-1-yl)(1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-497) and(4,4-difluoropiperidin-1-yl)(1-(3-(1-oxidothiazolidine-3-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-527) as off white solids.

Synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamidewith Amide Variation (MF-DH-405, 407, 448, 459, 477, 500 and MF-DH-501)

Provided below is an exemplary scheme to synthesize5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamidewith amide variations that are inhibitors of hydroxyprostaglandindehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinate(Int-2):(4,4-difluoropiperidin-1-yl)(H-pyrrolo[2,3-b]pyridin-5-yl)methanone (2g, 7.02 mmol, 1.0 eq) was converted to methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinateusing the general procedure for Ullmann coupling with methyl 5-bromonicotinate (2.412 g, 1.5 eq) and K3PO4 (2 eq). The product was obtained(1.31 g, 45.8%) as an off-white solid; LCMS 401.2 [M+H]⁺.

Step-2: synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinicacid (Int-3): methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinate (1.30 g, 3.24 mmol) was converted to5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinic acid using the general procedure for ester hydrolysis withLiOH. MF-DH-425 (Int-3) was isolated as an off-white solid (0.78 g,Yield 61%.), m/z=386.2 [M+H]⁺; HPLC purity 97.07%.

Step-3: Synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-neopentylnicotinamide/5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(pentan-3-yl)nicotinamide/N-(tert-butyl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide/6-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-ethylnicotinamide/N-(1-cyclopropyl-1H-pyrazol-3-yl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide/N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(MF-DH-405, 407, 448, 459, 477, 500 and MF-DH-501):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinicacid was converted to the title compounds using general procedure foramide coupling with HATU. This afforded final compounds as off-whitesolids.

Step-3: Synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(isoxazol-5-yl)nicotinamide(MF-DH-459); General procedure for amide coupling with POCl₃/pyridine:To the stirred solution of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinicacid (150 mg, 0.3 mmol) in pyridine (5 mL), POCl₃ (0.2 ml) was added at0° C. followed by isoxazol-5-amine (1.1 eq). The resulting reactionmixture was stirred for 30 min at room temperature. After completeconsumption of starting material, the mixture was poured into crushedice, the precipitate was filtered and washed with ether (50 mL). Thecrude was then purified by flash column chorography using 10%MeOH:CH₂Cl₂ to afford the title compound as an off white solid.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation (MF-DH-406, 422, 430, 437, 438, 429, and MF-DH-460)

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinate(Int-2):(4,4-difluoropiperidin-1-yl)(H-pyrrolo[2,3-b]pyridin-5-yl)methanone (2g, 7.02 mmol, 1.0 eq) was converted to methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinate using the general procedure for Ullmann coupling. Int-2 wasobtained (2.33 g, 77%) as an off-white solid; LCMS 401.2 [M+H]⁺.

Step-2: Synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinicacid (MF-DH-434, Int-3): Methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinate(2.30 g, 5.75 mmol) was converted to5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinic acid using the general procedure forester hydrolysis withLiOH. This afforded MF-DH-434 (Int-3) as an off-white solid (1.40 g,Yield 63%.), LCMS 386.2 [M+H]⁺; HPLC purity 99.07%.

Step-3: Synthesis ofN-(tert-butyl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinamide/6-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-ethylpicolinamide/5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(pentan-3-yl)picolinamide/5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-neopentylpicolinamide(MF-DH-406, MF-DH-422, MF-DH-437, and MF-DH-438):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinic acid was converted to the title compounds using the generalprocedure for amide coupling with HATU and correspondingt-Butylamine/ethylamine/3-aminopentane/neopentylamine (1.2 eq). Thisafforded final compounds as off white solids.

Step-3: Synthesis of1-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinamido)cyclopropane-1-carboxylicacid (MF-DH-460):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolicacid (150 mg, 0.3 mmol) was subjected to the general procedure for amidecoupling with POCl3/pyridine with isoxazol-5-amine (1.1 eq). The crudewas purified by flash column chromatography using 10% MeOH:CH₂Cl₂ toafford the desired compound as an off white solid.

Step-3 and 4: Synthesis of1-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinamido)cyclopropane-1-carboxylicacid (MF-DH-430):4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolicacid (Int-3) was converted to methyl ester of MF-DH-430 using thegeneral procedure for amide coupling with HATU followed by hydrolysisunder general procedure for ester hydrolysis with LiOH to afford finalcompound MF-DH-430 as an off white solid.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation (MF-DH-473, MF-DH-478, MF-DH-457, MF-DH-472 and MF-DH-479)

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of(4,4-difluoropiperidin-1-yl)(1-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-2):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) (5 g, 13.2 mmol, 1.0 eq) was converted to(4,4-difluoropiperidin-1-yl)(1-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-2) with 5-bromo-2-iodopyridine (5.87 g, 20.7 mmol, 1.1 eq) usingthe general Ullmann coupling conditions to afford (Int-2) (3.49 g,56.47% yield) as an off-white solid. LCMS: 68.13%; MS: m/z=469.0 [M+H]⁺.

Step-2: Synthesis of MF-DH-473, MF-DH-478, MF-DH-457, MF-DH-472 andMF-DH-479:(4,4-difluoropiperidin-1-yl)(1-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-2) was converted to the title compounds by using the generalprocedure for Ullmann coupling.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of(1-(5-aminopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-2):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) was converted to Int-2 with 5-bromo-3-aminopyridine using thegeneral Ullmann coupling conditions to afford the desired product(75.41%) as light brown solid. LCMS: 92.50%; MS: m/z=358.1 [M+H]⁴.

Step-2: Synthesis ofN-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)cyclopropanesulfonamide(MF-DH-484): To a stirred solution of(1-(5-aminopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-2) (100 mg, 0.28 mmol, 1.0 eq) in pyridine (2 mL) at 0° C. wasadded cyclopropanesulfonyl chloride (47 mg, 0.33 mmol, 1.2 eq) and thenstirred at room temperature for 16 h. The progress of the reaction wasmonitored with TLC and LCMS. The reaction was concentrated under reducedpressure. The crude was purified using flash chromatography to obtainMF-DH-484 (45.1 mg) as an off-white solid.

Step-3: Synthesis of ethyl(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate(MF-DH-485): To a stirred solution of Int-2 (150 mg, 0.4 mmol, 1.0 eq)in DCM (5 mL) at 0° C., ethyl chloroformate (68 mg, 0.6 mmol, 1.5 eq),pyridine (66 mg, 0.8 mmol, 2.0 eq) and DMAP (10 mg, catalytic) wereadded sequentially and then stirred at room temperature for 16 h. Theprogress of the reaction was monitored with TLC and LCMS. The reactionmixture was diluted with water and extracted with DCM (2×30 mL). Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated. The crude was purified using flash chromatographyaffording MF-DH-485 (116 mg, 64.6% yield) as an off-white solid.

Synthesis of pyrrolopyridine-5-carboxyamide analogs with amide/Arylvariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(Int-2):4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) (5 g, 18.8 mmol, 1.0 eq) was converted to5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(Int-2) using the general procedure for Ullmann coupling to afford 3 gof Int-2 (43.47%) as an off-white solid. LCMS: 92.4% MS: m/z=368.2[M+H]⁺.

Step-2: Synthesis of(1-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4,4-difluoropiperidin-1-yl)methanone(MF-DH-455) (General procedure for preparation of triazoles fromnitriles): To a stirred solution of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(0.15 g, 0.4 mmol, 1.0 eq) in n-Butanol (2 mL) at 0° C. was added sodiummethoxide (22 mg, 0.4 mmol, 1.0 eq) after 10 min, formyl hydrazine (24mg, 0.4 mmol, 1.0 eq) was added and heated to 120° C. for 16 h. Theprogress of the reaction was monitored with TLC and LCMS. The reactionmixture was concentrated under reduced pressure, diluted with water andextracted with EtOAc (2×20 mL). The combined extracts were dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude was purified using prep HPLC to MF-DH-455 (10 mg, 5.80% yield) asan off-white solid.

Step-3: Synthesis of(Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxypicolinimidamide(Int-3) (General procedure for the synthesis of1,2,4-oxadiazol-5(4H)-one from nitrile): To a stirred solution of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(130 mg, 0.35 mmol, 1.0 eq) in EtOH (5 mL) was added NH₂OH·HCl (65 m,0.9 mmol, 1.5 eq) and heated to 80° C. for 16 h. The progress of thereaction was monitored with TLC and LCMS. The reaction was concentratedunder reduced pressure, diluted with EtOAc (20 mL), washed with water(10 mL), then organic phase was dried over sodium sulfate, filtered andconcentrated to afford(Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxypicolinimidamide(Int-3, 100 mg, 70.9% yield) The crude was used in the next step withoutfurther purification.

Synthesis of3-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one(MF-DH-456): To a stirred solution of(Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxypicolinimidamide(Int-3, 50 mg, 0.12 mmol, 1.0 eq) in DCM (10 mL) at 0° C., was added CDI(24 mg, 0.14 mmol, 1.5 eq) and TEA (0.01 mL, 0.15 mmol, 1.5 eq) wasadded and stirred at room temperature for 16 h. The progress of thereaction was monitored with TLC and LCMS. The reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith EtOAc (10 mL). The combine extracts were dried over sodium sulfate,filtered and concentrated. The crude was purified using prep HPLC, toobtain3-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one(MF-DH-456) (5 mg, 9.4% yield) as an off-white solid.

Step-4: Synthesis of(4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-471), (General procedure for the synthesis of5-methyl-1,2,4-oxadiazole from nitrile): To a stirred solution of((Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxypicolinimidamide(Int-3)(200 mg, 0.53 mmol, 1.0 eq) in acetic acid (10 mL), aceticanhydride was added and heated to 100° C., for 16 h. The reactionmixture was concentrated under reduced pressure, diluted with water andextracted with ethyl acetate. The combined extracts were washed withNaHCO₃ solution, water and dried over sodium sulfate, filtered andconcentrated. The crude was purified by prep HPLC to obtain(4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-471) (50 mg, 22.52% yield) as an off-white solid.

Step-5: Synthesis of(1-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(MF-DH-452)(General procedure for preparation of tetrazole fromnitriles): To a suspension of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile (50 mg, 0.7 mmol, 1.0 eq) in DMF:water (5 mL), NaN₃ (22mg, 1.4 mg, 2.0 eq) was added and stirred at 100° C. for 16 h. This wasextracted with EtOAc, concentrated, filtered and washed with ACN andmethanol affording(1-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(MF-DH-452, 42 mg, 45.3% yield) as an off-white solid.

Synthesis of(1-(5-(1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone/3-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-1,2,4-oxadiazol-5(4H)-one/(4,4-difluoropiperidin-1-yl)(1-(5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile(Int-2):4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) (1.6 g, 6.0 mmol, 1.0 eq) was converted to5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrileusing general procedure for Ullmann coupling to afford 3 g of Int-2(1.52 g, 72%) as an off-white solid. LCMS: 96.3%; MS: m/z=368.2 [M+H]⁺.

Step-2: Synthesis of(1-(5-(1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(MF-DH-453):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrilewas converted to(1-(5-(1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanoneusing the general procedure to prepare tetrazole from nitriles to affordan off-white solid.

Step-2 and 3: Synthesis of3-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one(MF-DH-454):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile was converted to((Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxynicotimamideusing the general procedure to make 1,2,4-oxadiazol-5(4H)-one fromnitrile to afford an off-white solid.

Step-2 and 3: Synthesis of(4,4-difluoropiperidin-1-yl)(1-(5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-470):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrilewas converted to((Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxynicotinamideusing the general procedure to make 5-methyl-1,2,4-oxadiazole fromnitrile to afford MF-DH-470 as an off-white solid.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

Step-1: Synthesis of1-(tert-butyldimethylsilyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (Int-2):To a stirred solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Int-1) (10g, 65.7 mmol, 1.0 eq) in dry THF (100 mL) at 0° C., NaH (50% in paraffinoil, 3.1 g, 131.5 mmol, 2.0 eq) was added. After 10 min, TBDMSCl (15 g,98.5 mmol, 1.5 eq) was added and stirred at room temperature for 16 h.The progress of the reaction was monitored with TLC and LCMS; after theconsumption of starting material, the reaction mixture was quenched withice water and extracted with EtOAc (2×50 mL). The combined organicphases were washed with water and brine. The organics were dried oversodium sulfate, filtered and concentrated to obtain a sticky liquid. Thecrude 10 g was used in the next step without further purification.

Note: The Int-2 is not stable at room temperature and was usedimmediately in the next step.

Step-2: Synthesis of ethyl1-(tert-butyldimethylsilyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate(Int-3): To a stirred solution of1-(tert-butyldimethylsilyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine Int-2(8.2 g, 36.67 mmol, 1.0 eq) in dry THF (100 mL) at −78° C., sec-BuLi(1.6 M in cyclohexane, 2.0 eq) was added dropwise and stirred for 30min. Ethyl chloroformate (6.08 g, 55 mmol, 1.5 eq) in THF (20 mL) wasadded at −78° C. and stirred for 2 h. The progress of the reaction wasmonitored with TLC. The reaction was quenched with saturated ammoniumchloride and extracted with EtOAc (2×20 mL). The combined extracts werewashed with water and brine, dried over sodium sulfate and concentratedto afford Int-3 (7.15 g) as a sticky liquid which was used in the nextstep without further purification.

Step-3: Synthesis of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (Int-4): Int-3 (7 g, 20.3 mmol, 1.0 eq) was converted to Int-4using the general procedure for ester hydrolysis with NaOH to afford(4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-4) as a paleyellow solid. (3.1 g, 73% yield) MS: m/z=197.1 [M+H]⁺, 198.1 [M+H]⁺.

Step-4: Synthesis of(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(Int-5): 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Int-4)(3.01, 153 mmol, 1.0 eq) was converted to(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone usingthe general procedure for amide coupling with HATU to afford Int-5 as anoff-white solid. MS: m/z=265.1 [M+2H]⁺.

Step-5: Synthesis of(4-(benzylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanoneInt-6: In a microwave vial, to a solution of(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(Int-5)(200 mg×5, 0.76 mmol, 1.0 eq) in n-BuOH (5 mL) was added benzylamine (89 mg x7, 0.83 mmol, 1.1 eq) and DIPEA (190 mg×7, 1.52 mmol, 2.0eq). The reaction was irradiated in microwave for 2 h at 150° C.Progress of the reaction was monitored with TLC and LCMS. The reactionwas concentrated under reduced pressure. The crude was purified usingcombi flash to afford(4-(benzylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(Int-6) (640 mg, 51% yield) as a yellow solid. MS: m/z=335.2 [M+H]⁺.

Step-6: Synthesis of(4-(benzylamino)-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone (MF-DH-385): Int-6 was converted to MF-DH-385 with 4-bromoanisole (840 mg, 0.35 mmol, 1.2 eq) using the general procedure forUllmann coupling to afford the desired product (550 mg, 45.8% yield) asan off-white sticky solid.

Step-7: Synthesis of(4-amino-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-290) (General procedure for debenzylation): To a solution of(4-(benzylamino)-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl) methanone (MF-DH-385)(100 mg, 0.22 mmol, 1.0 eq) inTHF:MeOH (1:1, 10 mL), 10% Pd/C (10 mg) was added and stirred underHydrogen (balloon pressure) for 12 h. The progress of the reaction wasmonitored with TLC and LCMS. The reaction mixture was filtered through acelite bed and concentrated and then purified using flash chromatographyto afford MF-DH-290 as a sticky liquid (24 mg, 30% yield).

Step-8: Synthesis of(4-amino-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(MF-DH-288) (General procedure for conversion of aryl amines to hydroxylamines via diazotization): To a stirred solution of4-amino-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone,MF-DH-290 (100 mg, 0.28 mmol) in acetic acid/water (1:1, 5 mL) at 0° C.was added NaNO₂ (48 mg, 0.56 mmol, 2.0 eq) and heated to 100° C. for 16h. The progress of the reaction was monitored with LCMS, NaHCO₃ wasadded and the mixture extracted with 10% MeOH/DCM. The organic phase wasdried over sodium sulfate, filtered and concentrated. The crude waspurified using Prep-HPLC to afford MF-DH-288 as sticky liquid.

Step-9: Synthesis of5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile(Int-7): To a stirred solution of(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone(Int-5)(340 mg, 1.29 mmol, 1.0 eq) in dry DMA (10 mL), Pd₂(dba)₃ (0.1eq), Zn (1.2 eq), Zn(CN)₂ (1.2 eq) were added under argon atmosphere andthen purged for 10 min. The resulting reaction mixture was heated to100° C. for 16 h. The progress of the reaction was monitored with TLCand LCMS; after the consumption of starting material, the reactionmixture was quenched with ice water and extracted with EtOAc (2×50 mL).The combined organic phases were washed with water and brine, dried oversodium sulfate, filtered and concentrated and then flash columnpurification afforded 135 mg of Int-7. MS: m/z=255.1 [M+H]⁺.

Step-10: Synthesis of1-(4-methoxyphenyl)-5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile(MF-DH-289):5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (130mg, 0.51 mmol) was converted to1-(4-methoxyphenyl)-5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrileusing the general procedure for Ullmann coupling to afford MF-DH-289.

Synthesis of4-(5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)benzonitrile/4-(5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzonitrile

Step-1: Synthesis of(4-fluoropiperidin-1-yl)(1H-pyrrolo[3,2-b]pyridin-5-yl)methanone/(4-fluoropiperidin-1-yl)(H-pyrrolo[2,3-c]pyridin-5-yl)methanone(Int-2): Int-1 was converted to Int-2 using the general method foracid/amine coupling with HATU to afford the desired product.

Step-2: Synthesis of MF-DH-462 and MF-DH-463: Int-2 was converted toMF-DH-462 and MF-DH-463 using the general procedure for Ullmann couplingdescribed previously.

Synthesis of((2R,6S)-2,6-dimethylpiperidin-1-yl)(1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone/((3R,5S)-3,5-dimethylpiperidin-1-yl)(1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone/4-(5-((3R,5S)-3,5-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile/4-(5-((3R,5S)-3,5-dimethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide

Step-1: Synthesis of (Int-2): 1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid was converted to Int-2 using general procedure for amide couplingwith HATU and the appropriate piperidine to afford Int-2 as an off-whitesolid.

Step-2: Synthesis of((2R,6S)-2,6-dimethylpiperidin-1-yl)(1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone/((3R,5S)-3,5-dimethylpiperidin-1-yl)(1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone/4-(5-((3R,5S)-3,5-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile:Int-2 was converted to the title compounds using the general procedurefor Ullmann coupling to afford MF-DH-328, MF-DH-329 and MF-DH-417 afterpurification.

Step-3: Synthesis of4-(5-((3R,5S)-3,5-dimethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-395):4-(5-((3R,5S)-3,5-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrilewas converted to4-(5-((3R,5S)-3,5-dimethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamideusing the general procedure for oxidation of nitriles to amides toafford MF-DH-395 as sticky solid.

Synthesis of4-(5-(4,4-difluoropiperidine-1-carbonothioyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(MF-DH-449)

The synthesis of Int-1 is described previously under Scheme 45.

Step-1: Synthesis of(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanethione(4,4-difluoropiperidin-1-yl) (Int-2): To a stirred solution of(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1)(400 mg, 1.5 mmol, 1.0 eq) in toluene (8 mL), Lawesson's reagent(1.21 g, 3.0 mmol, 2.0 eq) was added and heated to 120° C. for 4 h. Theprogress of the reaction was monitored with TLC and LCMS. The reactionmixture was diluted with water (20 mL) and EtOAc (50 mL). The EtOAclayer was separated, washed with water and brine. The organic phase wasdried over sodium sulfate, filtered and concentrated. The crude waspurified using combi-flash to afford(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanethione(4,4-difluoropiperidin-1-yl) (Int-2) (220 mg, 63% yield) as an off-whitesolid. LCMS: 94.2%; MS: m/z=282.1 [M+H]⁺.

Step-2: Synthesis of4-(5-(4,4-difluoropiperidine-1-carbonothioyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(MF-DH-449):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanethione(4,4-difluoropiperidin-1-yl)(Int-2)(30 mg, 0.1 mmol, 1.0 eq) wasconverted to4-(5-(4,4-difluoropiperidine-1-carbonothioyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrileby using the general procedure for Ullmann coupling to afford MF-DH-449(5.0 mg, 12.8% yield) as an off-white solid.

Synthesis of(1-(3-chloro-5-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone/3-chloro-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzamide

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of methyl3-chloro-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(400 mg, 1.4 mmol) was converted to methyl3-chloro-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2) using the general procedure for Ullmann coupling to obtain Int-2(210 mg, 32%) as an off-white solid/sticky liquid. MS: m/z=435.1[M+2H]⁺.

Step-2 and 3: Synthesis of((1-(3-chloro-5-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone/3-chloro-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzamide(MF-DH-481 and MF-DH-508): methyl3-chloro-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2) was subjected to the general procedure for ester hydrolysisusing LiOH, followed by the general procedure for amide coupling withHATU to obtain MF-DH-481 and MF-DH-508 as off white solids.

Synthesis of2-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-2-methylpropanenitrileand2-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-2-methylpropanamide(MF-DH-509 and MF-DH-487)

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of2-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-2-methylpropanenitrile(MF-DH-509): (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)(Int-1) was converted to2-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-2-methylpropanenitrile(MF-DH-509) by reacting with2-(5-bromopyridin-3-yl)-2-methylpropanenitrile using the generalprocedure for Ullmann coupling to afford MF-DH-509 (54.6% yield) as anoff-white sticky solid.

Step-2: Synthesis2-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-2-methylpropanamide(MF-DH-487):2-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-2-methylpropanenitrilewas converted to2-(5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)-2-methylpropanamideusing the general procedure for oxidation of nitrile to amide to affordMF-DH-487 as off-white solid.

Synthesis of4-(5-(4-fluoropiperidine-1-carbonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-380)

Step-1: Synthesis of(4-fluoropiperidin-1-yl)(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-2): Int-1 was converted to(4-fluoropiperidin-1-yl)(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneusing the general procedure for HATU acid/amine coupling described aboveto afford Int-2 (63%) as a brown sticky solid. MS: m/z=262.2 [M+H]⁺.

Step-2: Synthesis of4-(5-(4-fluoropiperidine-1-carbonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(MF-DH-387):(4-fluoropiperidin-1-yl)(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanonewas converted to4-(5-(4-fluoropiperidine-1-carbonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrileusing the general procedure for Ullmann coupling to afford MF-DH-387 asan off-white solid.

Step-3: Synthesis4-(5-(4-fluoropiperidine-1-carbonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-380):4-(5-(4-fluoropiperidine-1-carbonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrilewas converted to4-(5-(4-fluoropiperidine-1-carbonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamideusing the general procedure for oxidation of nitrile to amide affordingMF-DH-380 as an off-white solid.

Synthesis of4-(3-chloro-5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide/4-(3-chloro-5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide/4-(3-chloro-5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide(MF-DH-382 and MF-DH-383)

Steps 1 and 2 leading to Int-3 are described in Scheme 20 (X, X′=H) andScheme 31 (X=H, X′=F).

Steps 3 and 4: Int-3 was subjected to the general procedure for Ullmanncoupling to afford Int-4 (62% yield; MS: m/z=365.1 [M+H]⁺) and MF-DH-388(57% yield; MS: m/z=383.2 [M+H]⁺). Int-4 and MF-DH-388 were subjected tothe general procedure for oxidation of the nitrile to amide to affordthe title compounds MF-DH-383 and MF-DH-382.

Synthesis of(3-chloro-1-(6-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone/(3-chloro-1-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone

Step-1: The synthesis of Int-1 is described in Scheme 20.

Step-2: Int-1 was converted to Int-2 using the general procedure forHATU acid-amine coupling affording Int-2 as an off-white solid. MS:m/z=281.1 [M+H]⁺.

Step-3: Int-2 was converted to MF-DH-166 and MF-DH-169 using the generalprocedure for Ullmann coupling afforded the desired products asoff-white solids.

Synthesis of(4-fluoropiperidin-1-yl)(3-methyl-1-(pyrazin-2-yl)-1H-indol-5-yl)methanone/(4-fluoropiperidin-1-yl)(3-methyl-1-(pyrimidin-5-yl)-1H-indol-5-yl)methanone/(4-fluoropiperidin-1-yl)(1-(4-methoxyphenyl)-3-methyl-1H-indol-5-yl)methanone

Step-1: Synthesis of (3-methyl-1H-indol-5-yl)(piperidin-1-yl)methanone(Int-1): 3-methyl-1H-indole-5-carboxylic acid (SM-1) was converted toInt-1 using the general procedure for HATU acid-amine coupling describedearlier using 4-fluoro piperidine affording Int-2 as an off white solid.(68.1% yield, MS: m/z=261.1 [M+H]⁺).

Step-2: Synthesis of(4-fluoropiperidin-1-yl)-3-methyl-1-(pyrimidin-5-yl)-1H-indol-5-yl)methanone/(4-fluoropiperidin-1-yl)(3-methyl-1-(pyrazin-2-yl)-1H-indol-5-yl)methanone/(4-fluoropiperidin-1-yl)(1-(4-methoxyphenyl)-3-methyl-1H-indol-5-yl)methanone:Int-1 was converted to MF-DH-178, MF-DH-180, MF-DH-190 using the generalprocedure for Ullmann coupling described earlier using 5-iodopyrimidine,2-iodopyrazine and 1-iodo-4-methoxybenzene affording MF-DH-178,MF-DH-180, MF-DH-190 respectively as off-white solids.

Synthesis of(4-fluoropiperidin-1-yl)(3-(4-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone/(4-fluoropiperidin-1-yl)(3-(3-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone/(4-fluoropiperidin-1-yl)(3-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone(4-fluoropiperidin-1-yl)(3-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone

Step-1: Synthesis of 3-Iodo-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid(Int-1): To a preheated solution (40° C.) of1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (1 g, 6.16 mmol, 1 eq) inDMF (10 mL), N-Iodosuccinimide (1.66 g, 7.4 mmol, 1.2 eq) was added atroom temperature and the reaction mixture was heated at 60° C. for 3 h;after consumption of starting material, the reaction mixture was allowedto sit for 12 h without stirring. The mixture was quenched with icewater (30 mL) and extracted with DCM (2×30 mL). The combined organicextracts were washed with ice water (2×20 mL) and brine (10 mL), driedover sodium sulfate, filtered and concentrated in vacuo to obtain Int-1(1.3 g; Yield: 73%) as a light-yellow solid. MS: m/z=286.8 [M−H]⁺.

Step-2: Synthesis of(4-fluoropiperidin-1-yl)(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone(Int-2): 3-Iodo-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (Int-1) (1eq.) was converted to(4-fluoropiperidin-1-yl)(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)methanoneusing the general procedure for acid-amine coupling with HATU to afford(Int-2) as an off-white solid. MS: m/z=373.9 [M+H]⁺.

Step-3: Synthesis of(4-fluoropiperidin-1-yl)(3-iodo-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone(Int-3): To a stirred solution of(4-fluoropiperidin-1-yl)(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone(1 eq.) in THF at 0° C., NaH (1.5 eq) was added and stirred for 10minutes followed by the addition of methyl iodide (1.5 eq.) drop wise atthe same temperature. The reaction mixture was then stirred for 2 h.After complete consumption of the starting material, the reactionmixture was quenched with ice water and extracted with EtOAc. Thecombined organic extracts were washed with ice water and brine; driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyaffording(4-fluoropiperidin-1-yl)(3-iodo-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone(Int-3) as off-white solid. MS: m/z=388.1 [M+H]⁺.

Step-4: Synthesis of(4-fluoropiperidin-1-yl)(3-(4-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone/(4-fluoropiperidin-1-yl)(3-(3-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone/(4-fluoropiperidin-1-yl)(3-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methanone(MIF-DH-181, MF-DH-199 and MF-DH-200):(4-Fluoropiperidin-1-yl)(3-iodo-1-methyl-H-pyrrolo[3,2-b]pyridin-6-yl)methanone(Int-3) was subjected to the general procedure for Suzuki coupling withthe appropriate phenyl boronic acids. The crudes were purified throughsilica gel column chromatography to obtain the desired products.

Synthesis of((4-fluoropiperidin-1-yl)/((piperidin-1-yl)/(1H-benzo[d][1,2,3]triazol-5-yl)Analogs with Aryl/Amide Variation

Provided below is an exemplary scheme to synthesize((4-fluoropiperidin-1-yl/((piperidin-1-yl)/(1H-benzo[d][1,2,3]triazol-5-yl)analogs with aryl/amide variations that are inhibitors ofhydroxyprostaglandin dehydrogenase.

Step-1: Synthesis of Int-2: methyl 1H-indazole-5-carboxylate (1 eq) wasconverted to methyl 3-chloro-1H-indazole-5-carboxylate using the generalprocedure for chlorination with NCS affording Int-2 (43.2% yield, MS:m/z=212.2 [M+2a]⁺).

Step-2: Synthesis of Int-3a and Int-3b: Methyl1H-indazole-5-carboxylate/methyl 3-chloro-1H-indazole-5-carboxylate wereconverted to Int-3a (R=H)/Int-3b (R=Cl) using the general procedure forester hydrolysis with NaOH to afford Int-3a (73.0% yield, MS: m/z=163.1[M+H]⁺) and Int-3b (69.6% yield, MS: m/z=198.1 [M+2H]⁺).

Step-3: 1H-indazole-5-carboxylic acid(Int-3a)/3-chloro-1H-indazole-5-carboxylic acid (Int-3b) was convertedto Int-4a (R=H, X=H)/Int-4b (R=Cl, X=H)/Int-4c (R=H, X=F)/Int-4d (R=Cl,X=F) using the general procedure of amide coupling with HATU to affordInt-4a (72.3% yield, MS: m/z=230.1 [M+H]⁺), Int-4b (68.0% yield, MS:m/z=265.1 [M+2H]⁺), Int-4c (72.0% yield, MS: m/z=248.2 [M+H]⁺), andInt-4d (67.2% yield MS: m/z=283.2 [M+2H]⁺) as off-white solids.

Step-4: Synthesis of MF-DH-245, MF-DH-292, MF-DH-293, MF-DH-341,MF-DH-246, MF-DH-247, MF-DH-271, MF-DH-272: Int-4 was converted toMF-DH-245, MF-DH-392, MF-DH-293, MF-DH-341, MF-DH-246, MF-DH-247,MF-DH-271, MF-DH-272 using the general procedure for Ullmann coupling.

Synthesis of(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone(MF-DH-241)

Step-1: Synthesis of methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate(Int-2): To a stirred solution of methylimidazo[1,2-a]pyridine-7-carboxylate (1 eq.) in EtOAc (10 v), bromine(1.1 eq.) was added at 0° C. The reaction mixture was stirred for 1 h at0° C. After complete consumption of the starting material, the reactionmixture was quenched with sodium bisulfite and extracted with EtOAc(2×20 mL). The combined organic extracts were washed with ice water andbrine, dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography affording methyl3-bromoimidazo[1,2-a]pyridine-7-carboxylate (Int-2) as an off-whitesolid. MS: m/z=256.1 [M+2H]⁺.

Step-2: Synthesis of3-(4-methoxyphenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (Int-3):Methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate (Int-2) was convertedto 3-(4-methoxyphenyl)imidazo[1,2-a]pyridine-7-carboxylic acid usinggeneral procedure for Suzuki coupling to afford Int-3 as an off whitesolid. MS: m/z=269.1 [M+H]⁺.

Step-3: Synthesis of(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone(MF-DH-241): 3-(4-methoxyphenyl)imidazo[1,2-a]pyridine-7-carboxylic acid(Int-3) was converted to(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-7-yl)(piperidin-1-yl)methanone(MF-DH-241) using general procedure for HATU acid-amine couplingaffording the desired product as an off-white solid.

Synthesis of(4-fluoropiperidin-1-yl)(1-(4-methoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-yl)methanone/(1-(4-methoxyphenyl)-1H-benzo[d][1,2,3]triazol-5-yl)(piperidin-1-yl)methanone

The synthesis of Int-3 is described in Scheme 7.

Step-3: Synthesis of methyl1-(4-methoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (Int-4):methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (Int-3) (1.0 eq) wasconverted to methyl1-(4-methoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate usingaqueous solution of NaNO₂ (2.0 eq) and Conc. HCl (1 mL) at −5° C. for 12h to afford Int-4 (51.0% yield, MS: m/z=284.1 [M+H]⁺).

Step-4: Synthesis of1-(4-methoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid(Int-5): Methyl3-chloro-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-4) was converted to1-(4-methoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid usinggeneral ester hydrolysis procedures with LiOH affording Int-5 (73.0%yield, MS: m/z=270.3 [M+H]⁺) as an off white solid.

Step-5: Synthesis of MF-DH-242 and 243:1-(4-methoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid wasconverted to MF-DH-242 and 243 using the general procedure foracid-amine coupling with HATU.

Synthesis of(2-(3-hydroxy-3-methylbutyl)-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone/4-(5-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbutyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile/3-(1-(4-cyanophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propanamide

Step-A: Synthesis of methyl pent-4-ynoate (Int-A): To the stirredsolution of pent-4-ynoic acid (SM-1)(5 g, 50.9 mmol) in DCM (45 mL) wasadded oxalyl chloride (6.1 g, 50.9 mmol, 1 eq) dropwise at 0° C., andthe reaction mixture was stirred at 0° C. for 1 h. The reaction wasmonitored by TLC; upon completion, the reaction was cooled to roomtemperature and the volatiles were evaporated. The mixture wasredissolved in DCM (45 mL). MeOH (5 eq) was added and the reactionmixture was stirred at room temperature for 5 h. The mixture wasconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 10% EtOAc:Hex to obtainmethyl pent-4-ynoate (Int-A, 5.08 g, 89%) as a yellow liquid.

Step-B: Synthesis of 2-methylhex-5-yn-2-ol (Int-B): To a stirredsolution of methyl pent-4-ynoate (Int-A, 3.36 g, 10 mmol, 1 eq) in THF(15 mL) was added MeMgBr (2M in THF, 3 eq) portionwise at 0° C. over 15min. The reaction mixture was stirred for 5 h at room temperature. Thereaction was monitored by LCMS/TLC; upon completion, the reactionmixture was quenched with saturated NH₄Cl solution (20 mL) and extractedwith EtOAc (2×20 mL). The combined organic extracts were washed withbrine solution (20 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to afford the crude. The crude wasfurther purified by flash chromatography using 30% EtOAc:Hex to afford2-methylhex-5-yn-2-ol (Int-B, 1.93 g, 57.6%) as a light brown liquid.

Step-1: Synthesis of methyl 5-bromo-6-chloronicotinate (Int-2): Methyl5-bromo-6-chloronicotinate (1 g, 1 eq) was converted to5-bromo-6-chloronicotinic acid (Int-2) using general procedure for esterhydrolysis with LiOH affording Int-2 (66.3% yield; MS: m/z=236.1[M+H]⁺)as an off-white solid.

Step-2: Synthesis of(5-bromo-6-chloropyridin-3-yl)(piperidin-1-yl)methanone (Int-3a, X,X′=H) and(5-bromo-6-chloropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-3b, X, X′=F): 5-bromo-6-chloronicotinic acid (Int-2) was convertedto Int-3a (X, X′=H, 53% yield, MS: m/z=304.1[M+2H]⁺) and Int-3b (X,X′=F, 46.5% yield, MS: m/z=339.1[M+H]⁺, 340.1[M+2H]⁺) using generalprocedure for HATU acid-amine coupling.

Step-3: Synthesis of(5-bromo-6-((4-methoxyphenyl)amino)pyridin-3-yl)(piperidin-1-yl)methanone(Int-4a) and4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzonitrile(Int-4b); general procedure for SNAr #3: To a stirred solution of4-amino benzonitrile (1 eq.) in DMF (10 v), NaH (1.5 eq.) was addedportion wise at 0° C. and the reaction was stirred for 10 mins followedby addition of(5-bromo-6-chloropyridin-3-yl)(4,4-difluoropiperidin-1yl)methanone(Int-3) at 0° C. The reaction mixture was then stirred at 100° C. for 24h. The progress of the reaction was monitored by crude LCMS/TLC; aftercomplete consumption of the starting material, reaction mixture wasquenched with ice water (30 mL) and extracted with EtOAc (2×30 mL). Thecombined organic extracts were washed with ice water (2×20 mL) and brine(10 mL), dried over sodium sulfate, filtered and concentrated in vacuoto afford Int-4a (X, X′=H, 41.5% yield, MS: m/z=390.1[M+H]⁺) and Int-4b(X, X′=F, 32.5% yield, MS: m/z=421.1[M+2H]⁺).

Step-4: Synthesis of(2-(3-hydroxy-3-methylbutyl)-1-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(piperidin-1-yl)methanone/4-(5-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbutyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(MF-DH-330, MF-DH-44) (General procedure for Sonogashira coupling):(5-bromo-6-((4-methoxyphenyl)amino)pyridin-3-yl)(piperidin-1-yl)methanone(Int-4a)/4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzonitrile(Int-4b) was subjected to Sonogashira coupling with 1 eq. alkyne (B/A),Pd(PPh₃)₄ (0.1 eq), CuI (0.2 eq) and TEA (3 eq) in dioxane (5 v) at 100°C. for 12 h affording MF-DH-330, MF-DH-444 and methyl3-(1-(4-cyanophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propanoate.

Synthesis of3-(1-(4-cyanophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propanamide(MF-DH-446): methyl3-(1-(4-cyanophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propanoatewas converted to3-(1-(4-cyanophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propanoicacid using general procedure for ester hydrolysis with LiOH affordedacid; the acid was then converted to3-(1-(4-cyanophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propanamide(MF-DH-446) by using acid-amine (NH₄Cl) coupling with HATU affordingMF-DH-446.

Synthesis of(4,4-difluoropiperidin-1-yl)(1-(6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-465)

Step-1: Synthesis of Int-2: Int-2 was synthesized by using the generalUllmann coupling condition of Int-1 with 5-bromo-2-iodopyridine followedby purification to afford Int-2 (2.95 g) as an off-white solid. MS:m/z=469.0 (M+H).

Step-2: Synthesis of MF-DH-465:(4,4-difluoropiperidin-1-yl)(l-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanonewas converted to(4,4-difluoropiperidin-1-yl)(1-(6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneusing the general procedure for Sonogashira coupling to affordMF-DH-465.

Step-3: Synthesis of 3-methyl-3-(methylsulfonyl)but-1-yne (Int-3): To astirred solution of 3-chloro-3-methylbut-1-yne (5 g, 48.73 mmol, 1.0 eq)in DMF (25 mL) was added sodium methane sulfonate (6 g, 58.47 mmol, 1.2eq) and Cu(I) Cl (0.48 g, 4.87 mmol, 0.1 eq) at 0° C. The reaction ofwas stirred at 50° C., for 16 h. Workup and then flash columnpurification afforded Int-3.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

Int-1a, Int-1b, and Int-1c were prepared by subjectingpiperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone/(4-fluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneto the general procedure for Ullmann coupling to afford Int-1a (64%yield, MS: m/z 350.1 [M+H]⁺); Int-1b (53% yield, MS: m/z 350.2 [M+H]⁺);and Int-1c (63% yield, MS: m/z 332.2 [M+H]⁺).

Step-1: Synthesis of MF-DH-351, MF-DH-355 and MF-DH-361: Int-1 wasconverted to4-(5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide/3-(5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide4-(5-(4-fluoropiperidine-1-carbonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide/5-(5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide/3-(5-(4-fluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide/5-(5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamideusing general procedure for oxidation of nitrile to amide affordingMF-DH-343, 345, 351, 355 and MF-DH-361 as off-white solids.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Int-1 was converted to Int-2 using the general procedure forUllmann coupling with the appropriate aryl bromide (48.3% yield, MS:m/z=410.1[M+H]⁺).

Step-2: Int-2 was subjected to the general procedure for esterhydrolysis with LiOH to afford MF-DH-469.

Step-3: Synthesis of MF-DH-362, MF-DH-363, MF-DH-368, and MF-DH-369:MF-DH-425 (synthesis described in Scheme 57) and MF-DH-433 (synthesisdescribed in Scheme 54) were converted to final compounds using generalprocedure for HATU acid-amine coupling affording MF-DH-362, MF-DH-363,MF-DH-368, MF-DH-369 as off-white solids.

Synthesis of pyrrolopyridine-5-carboxyamide Analogs with Amide/ArylVariation

Provided below is an exemplary scheme to synthesizepyrrolopyridine-5-carboxyamide analogs with amide/Aryl variations thatare inhibitors of hydroxyprostaglandin dehydrogenase.

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of MF-DH-366, MF-DH-440, MF-DH-439 and Int-2:4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1, 1.6 g, 6.0 mmol, 1.0 eq) was subjected to the general procedurefor Ullmann coupling with 4-bromobenzonitrile/6-bromonicotinonitrile/5-Bromo-N,N-dimethyl-Pyridine-2-amine/3-bromobenzonitrileto afford the title compounds (MF-DH-439, MF-DH-440, MF-DH-366) and3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(Int-2) as off-white solids.

Step-2: Synthesis of(1-(4-(2H-tetrazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone/(1-(3-(2H-tetrazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(MF-DH-514 and MF-DH-515):4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile/3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(Int-2) was converted to(1-(4-(2H-tetrazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone/(1-(3-(2H-tetrazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanoneby using the general procedure for the synthesis of tetrazole from anitrile to afford MF-DH-514 and MF-DH-515 as off white solids.

Step-2: Synthesis of(1-(5-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(MF-DH-516):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrilewas converted to(1-(5-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanoneby using general procedure for the synthesis of triazoles from nitrileaffording MF-DH-516 as an off white solid.

Synthesis of(4,4-Difluoropiperidin-1-yl)(1-(6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-519)

The SM (synthesis described in Scheme 45) was converted to Int-1 usingthe general procedure for Ullmann coupling with the appropriateheteroaryl bromide.

Step-1: Synthesis of(Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxypicolinimidamide(Int-2):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(Int-1)(200 mg, 0.54 mmol, 1.0 eq.) was converted to(Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxypicolinimidamideas described in the general procedure for the synthesis of1,2,4-oxadiazol-5(4H)-one from nitrile to afford 150 mg of(Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxypicolinimidamide,Int-2. LCMS: 87.94%, MS: m/z=401.2 [M+H]⁺.

Step-2: Synthesis of(4,4-difluoropiperidin-1-yl)(1-(6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-3): To a stirred solution of(Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′hydroxypicolinimidamide (Int-2)(150 mg, 0.3 mmol, 1.0 eq.) in toluene (3mL) was added trifluoro acetic anhydride (0.1 ml, 0.75 mmol, 1 eq.) at0° C. The reaction mixture was then heated to reflux for 16 h. Thereaction was monitored by crude LCMS/TLC; after complete consumption ofthe starting material, the reaction mixture was extracted with EtOAc.The combined organic extracts were washed with water (2×10 mL) and brine(10 mL), dried over sodium sulfate, filtered, and concentrated in vacuoto afford 150 mg of(4,4-difluoropiperidin-1-yl)(1-(6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-3) which was directly used for the next step. MS: m/z=479.1 [M+H]⁺.

Step-3: Synthesis of(4,4-difluoropiperidin-1-yl)(1-(6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-519): To a stirred solution of(4,4-difluoropiperidin-1-yl)(1-(6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-3)(150 mg, 0.31 mmol, 1.0 eq.) in methanol (2 mL), hydrazinehydrate (0.15 mg, 0.93 mmol, 3 eq.) was added at 0° C. The reactionmixture was stirred at room temperature for 16 h. The reaction wasmonitored by crude LCMS/TLC; after complete consumption of the startingmaterial, the reaction mixture was concentrated in vacuo and extractedwith EtOAc. The combined organic extracts were washed with ice water(2×10 mL) and brine (10 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 50% EtOAc/heptane toafford(4,4-difluoropiperidin-1-yl)(1-(6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5yl)methanone,MF-DH-519 as brown solid (12 mg, 8% yield). LCMS: 90.27%, MS: m/z=479.1[M+H]⁺.

Synthesis of(1-(5-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone/(1-(6-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(MF-DH-517 and MF-DH-518)

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile/5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(Int-2):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) was converted to5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile/5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(Int-2) using the general procedure for Ullmann reaction describedearlier using 5-bromonicotinonitrile/5-bromopicolinonitrile to affordInt-2a (57% yield; LCMS: 96.3%; MS: m/z=368.2 [M+H]⁺) and Int-2b (51%yield; LCMS: 92.4% MS: m/z=368.2 [M+H]⁺) as off white solids.

Step-2: Synthesis of(1-(5-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone/(1-(6-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone(MF-DH-517 and MF-DH-518) (General procedure for synthesis of5-cyclopropyl-1,2,4-triazoles from nitriles): To a solution of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile/5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile(Int-2) (150 mg, 0.40 mmol, 1.0 eq.) in DMSO (5 mL), Cs₂CO₃ (400 mg,1.22 mmol, 3 eq.), CuBr (38 mg, 0.1 eq) was added and the reactionmixture was then heated at 120° C. for 16 h under aerobic conditions.The reaction was monitored by crude LCMS/TLC; after complete consumptionof the starting material, the reaction mixture was cooled to roomtemperature, quenched with ice water (10 mL), and extracted with EtOAc.The organic extracts were washed with ice water (2×10 mL) and brine (10mL), dried over sodium sulfate, filtered, and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography followed by Prep-HPLC purification to afford MF-DH-517(8%) and MF-DH-518 (12%) as off-white solids.

Synthesis of(S)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (MF-DH-562)

Step-1: Synthesis of(S)-(3-methylpiperidin-1-yl)(H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1): 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (100 mg, 0.62 mmol,1.0 eq.) was converted to(S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneusing general procedure for acid-amine coupling using HATU (354 mg, 0.93mmol, 1.5 eq), (S)-3-methylpiperidine HCl (101 mg, 1.2 mmol, 1.2 eq) toafford (S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1, 100 mg, 66.23%) as abrown liquid. MS: m/z=244.1 [M+H]⁺.

Step-2: Synthesis of methyl(S)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2):(S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) (100 mg, 0.41 mmol, 1.0 eq.) was converted to methyl(S)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2) using the general procedure for Ullmann reaction describedearlier using methyl 4-bromobenzoate to afford Int-2 after purification(95 mg; 61.29% yield) as an off white solid. LCMS: 99.07%, MS: m/z=378.2[M+H]⁺.

Step-3: Synthesis of(S)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (MF-DH-562): Methyl(S)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-2) was converted to(S)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid using general procedure for ester hydrolysis using LiOH to afford(S)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (MF-DH-562, 43 mg, 49.3% yield) as an off white solid. LCMS:92.02%, MS: m/z=364.2 [M+H]⁺.

Synthesis of(S)-4-(5-(3-fluoropyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile/(R)-4-(5-(3-fluoropyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(MF-DH-574 and MF-DH-575)

Step-1: Synthesis of(3-fluoropyrrolidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1): 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (500 mg, 3.085mmol, 1 eq.) was converted to (3-fluoropyrrolidin-1-yl)(lH-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1) using the generalprocedure for acid-amine coupling with HATU and 3-fluoropyrrolidine·HClto afford Int-1 (500 mg 71.5%) as an off white solid; LCMS: 99.93%, MS:m/z=234.1 [M+H]⁺.

Step-2 and 3: Synthesis of both enantiomers of4-(5-(3-fluoropyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(MF-DH-574 and MF-DH-575):(3-Fluoropyrrolidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1) (430 mg, 1.8 mmol, 1.0 eq.) was converted to4-(5-(3-fluoropyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile(Int-2) using the general procedure for Ullmann reaction using 4-bromobenzonitrile to afford racemic Int-2 (220 mg; 36.5% yield) as an offwhite solid. The racemic product (Int-2) was separated via ChiralPrep-HPLC purification to get both the enantiomers separately, MF-DH-574and MF-DH-575.

Synthesis of4-(5-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbutyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (MF-DH-538)

Step-1: Synthesis of(5-bromo-6-chloropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-2): 5-bromo-6-chloronicotinic acid (Int-1) (2.0 g, 8.54 mmol, 1.0eq.) was converted to(5-bromo-6-chloropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-2) using the general procedure for amide coupling with HATU toafford5-bromo-6-chloropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanon, Int-2(1.8 g, 60% yield) as an off white solid. MS: m/z=338.2 [M+H]⁺, 339.0[M+2H]⁺.

Step-2: Synthesis of methyl4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzoate(Int-3):(5-bromo-6-chloropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-2)(400 mg, 1.55 mmol, 1.0 eq.) was subjected to the generalprocedure for SNAr reaction #3 to afford methyl4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzoate(Int-3) (200 mg, 37% yield). MS: m/z=454.1 [M+H]⁺, 455.0 [M+2H]⁺.

Step-3: Synthesis of methyl4-(2-(3-hydroxy-3-methylbutyl)-5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-4): methyl4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzoate(Int-3)(200 mg, 0.44 mmol, 1.0 eq.) was converted to methyl4-(2-(3-hydroxy-3-methylbutyl)-5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoateusing general procedure for Sonogashira coupling using2-methylhex-5-yn-2-ol (Int-B, previously described in the synthesis ofMF-DH-330) (148 mg, 1.32 mmol, 3.0 eq) to afford methyl4-(2-(3-hydroxy-3-methylbutyl)-5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-4, 70 mg, 35% yield) as a sticky liquid. MS: m/z=486 [M+H]⁺.

Step-4: Synthesis of4-(5-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbutyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid (MF-DH-538): Methyl4-(2-(3-hydroxy-3-methylbutyl)-5-(piperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate(Int-4) (70 mg, 0.14 mmol, 1.0 eq.) was converted to4-(5-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbutyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoicacid using general procedure for ester hydrolysis with LiOH to affordMF-DH-538 (28.4 mg, 43.0% yield) as a sticky liquid. MS: m/z=472.2[M+H]⁺.

Synthesis of4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile/4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-(5-hydroxy-5-methylhex-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(MF-DH-476 and MF-DH-544)

Step-1: Synthesis of methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate(Int-1): methyl 6-chloro-5-nitronicotinate (SM) (2 g, 9.23 mmol, 1.0eq.) was converted to methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate(Int-1) using the general procedure for SNAr #3 reaction with NaH and4-aminobenzonitrile (1.63 g, 13.85 mmol, 1.5 eq.) to obtain methyl6-((4-cyanophenyl)amino)-5-nitronicotinate (Int-1, 2.0 g, 72.4% yield).The crude was used in the next step without further purification. MS:m/z=299.1 [M+H]⁺.

Step-2: Synthesis of methyl 5-amino-6-((4-cyanophenyl)amino)nicotinate(Int-2): methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate (Int-1)(2 g,6.71 mmol, 1.0 eq) was converted to5-amino-6-((4-cyanophenyl)amino)nicotinate (Int-2) using the generalprocedure for reduction of nitro compounds using Fe to obtain5-amino-6-((4-cyanophenyl)amino)nicotinate (Int-2, 350 mg, 14% yieldafter two steps) as a gummy liquid/semi solid. MS: m/z=269.2 [M+H]⁺.

Step-3: Synthesis of methyl3-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-3):methyl 5-amino-6-((4-cyanophenyl)amino)nicotinate (Int-2) (350 mg, 1.5mmol, 1.0 eq) was converted to methyl3-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate by using thegeneral procedure for imidazole cyclisation with PTSA described forMF-PGDH-023 to obtain methyl3-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-3, 300mg, 84% yield) as a pale brown solid. MS: m/z=279.1 [M+H]⁺.

Step-4: Synthesis of3-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (Int-4):3-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-3)(250mg, 0.919 mmol, 1.0 eq) was converted to3-(4-cyanophenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (Int-4)using the general procedure for ester hydrolysis with LiOH to obtain4-cyanophenyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (Int-4, 200mg, 84% yield) as an off white solid. MS: m/z=262.1 [M−H]⁻.

Step-5: Synthesis of4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(Int-5): 4-cyanophenyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid(Int-4, 200 mg, 0.77 mmol, 1.0 eq) was converted to4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(Int-5) using the general acid-amine coupling using HATU to obtain4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(Int-5, 250 mg, 89.9% yield) as an off white solid. MS: m/z=368.2[M+H]⁺.

Step 6: Synthesis of4-(2-bromo-6-(4,4-difluoropiperidine-1-carbonyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(Int-6): To a stirred solution of4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(Int-5) (220 mg, 0.59 mmol, 1.0 eq) in THF (10 v) at room temperature,NBS (320 mg, 1.79 mmol, 3.0 eq) was added and then heated to 60° C. for3 h. The progress of the reaction was monitored by TLC and LCMS. Afterconsumption of SM, the reaction was diluted with water (20 ml) andextracted with EtOAc (2×30 mL). The combined extracts were washed withsodium thiosulfate solution (20 mL), dried over sodium sulfate,filtered, and concentrated. The crude was purified by combi-flashchromatography to afford4-(2-bromo-6-(4,4-difluoropiperidine-1-carbonyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(Int-6, 90 mg, 33% yield, MS: m/z=447.1 [M+H]⁺, 448.1 [M+2H]⁺) as abrown solid.

Step-7: Synthesis of4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile/4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-(5-hydroxy-5-methylhex-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(MF-DH-476 and MF-DH-544):4-(2-bromo-6-(4,4-difluoropiperidine-1-carbonyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile(Int-6, 80 mg, 0.18 mmol, 1.0 eq.) was converted to4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile/4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-(5-hydroxy-5-methylhex-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrileusing the general procedure for Sonogashira coupling with2-methylbut-3-yn-2-ol/Int-B (previously described in the synthesis ofMF-DH-330) to afford MF-DH-476 and MF-DH-544 as off white solids.

Synthesis of(4,4-difluoropiperidin-1-yl)(2-(3-hydroxy-3-methylbutyl)-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-542)

Step-1: Synthesis of4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzonitrile(Int-2):5-bromo-6-chloropyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-1) (1 g, 2.8 mmol) was converted to4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzonitrile(Int-2) using the general procedure for SNAr #3 reaction describedearlier using 4-aminobenzonitrile to afford4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzonitrile(Int-2, 510 mg; 43% yield, MS: m/z=422.2 [M+H]⁺, 423.1 [M+2H]⁺) as anoff white solid.

Step-2: Synthesis of4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)-N-hydroxybenzimidamide(Int-3):4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)benzonitrile(Int-2, 500 mg, 1.18 mmol, 1.0 eq.) was converted to4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)-N-hydroxybenzimidamideas described in the general procedure for the synthesis of1,2,4-oxadiazol-5(4H)-one from nitrile to afford Int-3 (400 mg, crude).The obtained crude of Int-3 was directly used for the next step. MS:m/z=455.1 [M+H]⁺, 456.2 [M+2H]⁺.

Step-3: Synthesis of(5-bromo-6-((4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)amino)pyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-4): To a stirred solution of4-((3-bromo-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)amino)-N-hydroxybenzimidamide(Int-3, 400 mg, 0.88 mmol, 1 eq.) in acetic acid (20 mL) was addedacetic anhydride (180 mg, 1.76 mmol, 1.0 eq.) at 0° C. The reactionmixture was then heated to reflux for 16 h. The reaction was monitoredby crude LCMS/TLC; after completion of the starting material, thereaction mixture was extracted with EtOAc. The combined organic extractswere washed with water (2×10 mL) and brine (10 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude was purifiedover combi-flash to afford to5-bromo-6-((4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)amino)pyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-4, 150 mg, 35.7% yield, MS: m/z=478.0 [M+H]⁺, 479.1 [M+2H]⁺).

Step-4: Synthesis of(4,4-difluoropiperidin-1-yl)(2-(3-hydroxy-3-methylbutyl)-1(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-542):(5-bromo-6-((4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)amino)pyridin-3-yl)(4,4-difluoropiperidin-1-yl)methanone(Int-4, 130 mg, 0.27 mmol, 1.0 eq.) was converted to(4,4-difluoropiperidin-1-yl)(2-(3-hydroxy-3-methylbutyl)-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanoneusing general procedure for Sonogashira coupling with2-methylhex-5-yn-2-ol (Int-B, previously described in the synthesis ofMF-DH-330)(92 mg, 0.82 mmol, 2.0 eq) to afford(4,4-difluoropiperidin-1-yl)(2-(3-hydroxy-3-methylbutyl)-1-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(MF-DH-542, 30 mg, 35% yield, LCMS: 96.8%, MS: m/z=510.1 [M+H]⁺) as awhite solid.

Synthesis ofN-(6-(tert-butyl)pyridin-3-yl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(MF-DH-520)

The synthesis of Int-1 is described in Scheme 45.

Step-1: Synthesis of methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-ylnicotinate(Int-2):(4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Int-1, 500 mg, 1.8 mmol, 1.0 eq.) was converted to methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinate(Int-2) using the general procedure for Ullmann reaction describedearlier, using methyl 5-bromonicotinate to afford methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinate(Int-2, 200 mg, 27.47% yield, MS: m/z=387.1 [M+H]⁺) as white solid.

Step-2: Synthesis of5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinicacid (Int-3): Methyl5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinate(Int-2, 200 mg, 0.58 mmol, 1.0 eq) was converted to5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinicacid using general procedure forester hydrolysis with LiOH to afford5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinicacid (Int-3, 100 mg, 50.2% yield, MS: m/z=387.1 [M+H]⁺) as off whitesolid.

Step-3: Synthesis ofN-(6-(tert-butyl)pyridin-3-yl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(MF-DH-520):5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinicacid (Int-3, 100 mg, 0.25 mmol, 1.0 eq.) was converted toN-(6-(tert-butyl)pyridin-3-yl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamideusing the general procedure of acid-amine coupling using POCl₃/pyridineto afford toN-(6-(tert-butyl)pyridin-3-yl)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(MF-DH-520, 18 mg, 13.4% yield, LCMS: 99.1%. MS: m/z=519.2 [M+H]⁺).

Example 2: hPGDH Inhibitor Screening Biochemical Assay

A hydroxyprostaglandin dehydrogenase inhibition screening biochemicalassay can be performed to assess the synthesized inhibitors providedherein. Provided herein is an exemplary biochemical assay for hPGDHinhibitor screening.

The in vitro biochemical assay can be performed in white, 384 plates intotal 20 μl reaction volume consisting of 10 nM of 15-PGDH/HPGD (R&DSystem #5660-DH), 15 μM Prostaglandin E2 (Sigma, Cat #P5640-10MG) and0.25 mM β-Nicotinamide adenine dinucleotide sodium salt (Sigma, Cat#N0632-5G) made in reaction buffer (50 mM Tris-HCl, pH 7.5, 0.01% Tween20) at 10-point dose response curve for test/tool compounds. Briefly, 5μl (4×) of compounds solution and 5 μl (final concentration, 10 nM) ofenzyme solution is added to white 384 well plates and incubated for 10mins at 37° C. 5 μl (4λ) of Prostaglandin E2 and 5 μl (4×) ofβ-Nicotinamide adenine dinucleotide sodium salt is added to the wellsand incubated for 10 mins at room temperature. Fluorescence is recordedat ex/em=340 nm/485 nm. The percentage (%) inhibition of enzyme activitywas determined relative to positive control (1% DMSO) and IC50 wascalculated using GraphPad prism software (four parameter-variable slopeequation). Exemplary data are shown in Table 4.

TABLE 4 hPGDH inhibition potency hPGDH: Average hPGDH: Average MoleculeName IC₅₀ (μM) Molecule Name IC₅₀ (μM) MF-DH-133 A MF-PGDH-047 CMF-DH-145 A MF-PGDH-050 C MF-DH-140 A MF-PGDH-035 A MF-DH-135 AMF-PGDH-024 A MF-DH-132 B MF-PGDH-088 B MF-DH-157 A MF-PGDH-048 BMF-DH-121 C MF-PGDH-090 C MF-DH-139 A MF-PGDH-091 A MF-DH-138 BMF-PGDH-049 A MF-DH-134 A MF-PGDH-046 B MF-DH-131 A MF-PGDH-032 BMF-DH-116 C MF-PGDH-064 C MF-DH-141 A MF-PGDH-065 C MF-DH-115 BMF-PGDH-063 B MF-DH-128 B MF-PGDH-052 B MF-DH-123 A MF-PGDH-045 BMF-PGDH-075 A MF-PGDH-034 A MF-PGDH-069 A MF-PGDH-033 A MF-PGDH-057 AMF-PGDH-007 A MF-DH-129 B MF-PGDH-040 B MF-DH-118 B MF-PGDH-039 AMF-PGDH-105 B MF-PGDH-038 A MF-PGDH-096 A MF-PGDH-030 A MF-PGDH-022 AMF-PGDH-042 C MF-PGDH-097 A MF-PGDH-027 A MF-PGDH-095 A MF-PGDH-037 AMF-PGDH-106 A MF-PGDH-041 A MF-PGDH-107 A MF-PGDH-043 B MF-PGDH-076 AMF-PGDH-036 A MF-PGDH-062 A MF-PGDH-026 A MF-PGDH-058 B MF-PGDH-018 AMF-PGDH-087 B MF-PGDH-023 A MF-PGDH-074 A MF-PGDH-019 A MF-PGDH-073 BMF-PGDH-017 B MF-PGDH-070 A MF-PGDH-016 A MF-PGDH-067 A MF-PGDH-015 AMF-PGDH-054 A MF-PGDH-014 A MF-PGDH-104 B MF-PGDH-005 A MF-PGDH-068 AMF-PGDH-021 B MF-PGDH-053 A MF-PGDH-020 A MF-PGDH-089 B MF-PGDH-012 AMF-PGDH-079 A MF-PGDH-011 A MF-PGDH-078 A MF-PGDH-009 A MF-PGDH-077 AMF-PGDH-008 A MF-PGDH-071 A MF-PGDH-006 A MF-PGDH-061 A MF-PGDH-004 AMF-PGDH-098 C MF-DH-146 A MF-DH-158 A MF-DH-160 B MF-DH-178 B MF-DH-130B MF-DH-180 B MF-DH-124 A MF-DH-169 A MF-DH-150 A MF-DH-166 A MF-DH-397A MF-DH-384 A MF-DH-367 A MF-DH-365 A MF-DH-389 A MF-DH-374 A MF-DH-370A MF-DH-369 A MF-DH-368 A MF-DH-347 A MF-DH-348 A MF-DH-345 A MF-DH-344A MF-DH-343 A MF-DH-342 A MF-DH-329 A MF-DH-327 C MF-DH-319 A MF-DH-340A MF-DH-328 B MF-DH-326 C MF-DH-317 A MF-DH-310 A MF-DH-309 A MF-DH-304A MF-DH-303 B MF-DH-337 A MF-DH-336 A MF-DH-325 C MF-DH-324 B MF-DH-323A MF-DH-322 A MF-DH-320 A MF-DH-318 A MF-DH-306 A MF-DH-302 A MF-DH-321A MF-DH-312 C MF-DH-307 A MF-DH-308 A MF-DH-305 A MF-DH-301 A MF-DH-300A MF-DH-299 A MF-DH-298 A MF-DH-311 C MF-DH-297 A MF-DH-296 A MF-DH-295A MF-DH-294 A MF-DH-285 A MF-DH-274 A MF-DH-275 A MF-DH-273 A MF-DH-250A MF-DH-251 A MF-DH-239 A MF-DH-191 A MF-DH-147 A MF-DH-149 C MF-DH-148C MF-DH-394 A MF-DH-375 B MF-DH-371 A MF-DH-366 A MF-DH-462 C MF-DH-449C MF-DH-448 A MF-DH-445 A MF-DH-439 A MF-DH-417 A MF-DH-406 A MF-DH-438A MF-DH-437 A MF-DH-434 A MF-DH-433 A MF-DH-422 A MF-DH-419 A MF-DH-412A MF-DH-411 A MF-DH-402 A MF-DH-270 A MF-DH-425 A MF-DH-424 A MF-DH-418A MF-DH-416 A MF-DH-413 A MF-DH-405 A MF-DH-376 B MF-DH-364 A MF-DH-409A MF-DH-407 A MF-DH-403 A MF-DH-396 A MF-DH-393 A MF-DH-355 A MF-DH-339A MF-DH-330 A MF-DH-288 C MF-DH-404 A MF-DH-392 A MF-DH-378 A MF-DH-362A MF-DH-359 A MF-DH-358 A MF-DH-357 A MF-DH-351 A MF-DH-400 A MF-DH-399A MF-DH-395 A MF-DH-394 A MF-DH-390 A MF-DH-375 B MF-DH-371 A MF-DH-366A MF-DH-363 A MF-DH-361 A MF-DH-341 B MF-DH-386 A MF-DH-290 A MF-DH-289A MF-DH-388 A MF-DH-387 A MF-DH-385 B MF-DH-527 A MF-PGDH-020 AMF-DH-393 A MF-PGDH-077 A MF-DH-396 A MF-PGDH-078 A MF-DH-403 AMF-PGDH-079 A MF-DH-407 A MF-DH-544 B MF-DH-409 A MF-DH-124 A MF-DH-364A MF-DH-130 B MF-DH-376 B MF-DH-166 A MF-DH-405 A MF-DH-169 A MF-DH-413A MF-DH-180 B MF-DH-418 A MF-DH-178 B MF-DH-402 A MF-DH-176 B MF-DH-411A MF-DH-117 C MF-DH-412 A MF-DH-175 A MF-DH-419 A MF-DH-184 B MF-DH-422A MF-DH-186 B MF-DH-433 A MF-DH-187 A MF-DH-434 A MF-DH-189 A MF-DH-437A MF-DH-193 A MF-DH-438 A MF-DH-195 B MF-DH-406 A MF-DH-199 B MF-DH-417B MF-DH-200 C MF-DH-439 A MF-DH-204 B MF-DH-448 A MF-DH-205 A MF-DH-449C MF-DH-181 B MF-DH-462 C MF-DH-185 C MF-DH-421 A MF-DH-190 A MF-DH-426A MF-DH-206 A MF-DH-427 B MF-DH-201 C MF-DH-429 A MF-DH-237 A MF-DH-450A MF-DH-218 B MF-DH-451 A MF-DH-219 A MF-DH-463 C MF-DH-224 B MF-DH-431A MF-DH-236 B MF-DH-432 A MF-DH-238 B MF-DH-440 B MF-DH-214 B MF-DH-441A MF-DH-215 A MF-DH-453 A MF-DH-216 B MF-DH-454 A MF-DH-217 A MF-DH-458A MF-DH-225 A MF-DH-467 B MF-DH-242 A MF-DH-430 A MF-DH-243 A MF-DH-442A MF-DH-222 B MF-DH-443 A MF-DH-223 A MF-DH-452 A MF-DH-228 B MF-DH-457A MF-DH-267 B MF-DH-459 A MF-DH-268 B MF-DH-468 A MF-DH-226 B MF-DH-469A MF-DH-227 B MF-DH-420 A MF-DH-229 B MF-DH-455 A MF-DH-246 B MF-DH-456A MF-DH-247 B MF-DH-464 A MF-DH-249 A MF-DH-465 B MF-DH-245 A MF-DH-471A MF-DH-272 B MF-DH-472 A MF-DH-271 B MF-DH-477 A MF-DH-287 A MF-DH-428A MF-DH-284 C MF-DH-460 A MF-DH-292 A MF-DH-470 A MF-DH-337 A MF-DH-480A MF-DH-340 A MF-DH-482 A MF-DH-346 A MF-DH-485 A MF-DH-380 A MF-DH-478A MF-DH-385 B MF-DH-479 A MF-DH-387 A MF-DH-481 A MF-DH-388 A MF-DH-484A MF-DH-389 A MF-DH-486 A MF-DH-289 A MF-DH-489 B MF-DH-290 A MF-DH-496A MF-DH-365 A MF-DH-498 A MF-DH-382 A MF-DH-499 A MF-DH-383 A MF-DH-500A MF-DH-397 A MF-DH-501 A MF-DH-361 A MF-DH-487 A MF-DH-363 A MF-DH-491A MF-DH-366 A MF-DH-507 A MF-DH-395 A MF-DH-508 A MF-DH-399 A MF-DH-509A MF-DH-400 A MF-DH-515 A MF-DH-351 A MF-DH-444 A MF-DH-362 A MF-DH-495A MF-DH-392 A MF-DH-514 A MF-DH-404 A MF-DH-521 A MF-DH-288 B MF-DH-446B MF-DH-330 A MF-DH-497 A MF-DH-355 A MF-DH-502 A MF-DH-424 A MF-DH-516A MF-DH-425 A MF-DH-575 A MF-DH-574 A MF-DH-562 A MF-DH-476 B MF-DH-542A MF-DH-519 A MF-DH-518 A MF-DH-538 A MF-DH-520 A MF-DH-517 A A < 0.1μM; 0.1 μM ≤ B < 1 μM; 1 μM ≤ C

Example 3: Liver Microsome Stability Assay

A microsomal mixture (microsomes and Kphos buffer) was prepared at aconcentration of 1.428 mg/mL in 2 mL tubes. To this microsomal mixture1.6 μL (1 mM) of test compound and positive control were spiked; fromthis mixture, 70 μL was transferred to 96 well plate and pre-incubatedat 37° C. for 5 min. After pre-incubation, the zero minute time pointreaction was stopped using 100 μL of ice-cold acetonitrile containinginternal standard and μL of NADPH (3.33 mM in Kphos buffer) was added.The 45 minute time point reaction was initiated by addition of 30 μL ofNADPH (3.33 mM in Kphos buffer) and incubated at 37° C. for 15 and 45min. Reactions without NADPH and buffer controls (minus NADPH) at 0, 15,and 45 minutes were also incubated to rule out non-NADPH metabolism orchemical instability in the incubation buffer. Incubation reactions werestopped with 100 μL of ice-cold acetonitrile containing internalstandard. The plates were centrifuged at 4000 RPM for 15 min and 100 μLaliquots were submitted for analysis by LC-MS/MS. (Verapamil in humanliver microsomes (HLM) and rat liver microsomes (RLM) was used aspositive controls. Imipramine in mouse liver microsomes (MLM) was usedas a positive control.) Samples were monitored for parent compounddisappearance in MRM mode (multiple reaction monitoring) using LC-MS/MS.The peak area ratios of analyte versus internal standard were used tocalculate the % remaining at the end of 45 minutes in the presence ofNADPH.

Exemplary data are shown in Table 5.

TABLE 5 Liver Microsome Stability HLM + MLM + RLM + NADPH (% NADPH (%NADPH (% Solubility: remaining remaining remaining Solubility atMolecule Name at 45 min) at 45 min) at 45 min) pH 7.4 (μM) MF-PGDH-02087 30 23 150 MF-PGDH-077 97 84 160 MF-PGDH-078 96 89 140 MF-PGDH-079 10087 140 MF-DH-124 48 34 MF-DH-130 68 74 MF-DH-166 47 33 MF-DH-169 71 69MF-DH-175 117 45 MF-DH-187 17 MF-DH-189 23 MF-DH-193 0 MF-DH-205 78MF-DH-190 29 MF-DH-206 9 MF-DH-201 48 MF-DH-237 0 MF-DH-218 34 MF-DH-21926 MF-DH-224 38 MF-DH-214 60 MF-DH-215 45 MF-DH-216 64 MF-DH-217 34MF-DH-225 40 MF-DH-242 51 MF-DH-243 34 MF-DH-223 74 MF-DH-228 69MF-DH-267 67 MF-DH-268 60 MF-DH-227 48 MF-DH-229 39 MF-DH-246 46MF-DH-247 22 MF-DH-249 29 MF-DH-245 16 MF-DH-287 44 MF-DH-292 27 69MF-DH-337 1 <5.0 MF-DH-380 89 75 MF-DH-387 72 MF-DH-365 41 MF-DH-382 26MF-DH-383 12 MF-DH-395 8 80 MF-DH-399 6 MF-DH-400 0 MF-DH-404 101 <5.0MF-DH-396 4 MF-DH-403 45 MF-DH-407 51 MF-DH-409 78 MF-DH-405 86MF-DH-413 94 MF-DH-411 87 MF-DH-412 97 MF-DH-422 87 MF-DH-434 94MF-DH-437 25 MF-DH-438 63 MF-DH-406 66 MF-DH-448 79 MF-DH-429 97MF-DH-453 116 >100 MF-DH-454 92 >100 MF-DH-458 68 62 MF-DH-467 90MF-DH-452 90 MF-DH-457 87 MF-DH-459 31 MF-DH-455 86 MF-DH-464 100MF-DH-471 99 MF-DH-472 83 MF-DH-428 97 MF-DH-470 74 MF-DH-482 103MF-DH-485 80 MF-DH-481 81 MF-DH-498 0 MF-DH-499 15 MF-DH-500 60MF-DH-507 97 MF-DH-508 37 MF-DH-515 103 MF-DH-514 110 MF-DH-521 84MF-DH-516 88 MF-DH-424 96 156 MF-DH-542 68 MF-DH-519 89 MF-DH-518 92MF-DH-538 91 MF-DH-520 38 MF-DH-517 47 HLM = human liver microsomes; MLM= mouse liver microsomes; RLM = rat liver microsomes

Example 4: A549 Cell-Based Assay

30,000 A549 cells per well were seeded into a tissue culture treatedflat bottom 96 well plate, and incubated for 24 hours in a 37° C., 5%CO₂ incubator. After 24 hours of incubation, complete media werereplaced with 100 μL of low serum (F12K+1% FBS) media and the plate wasincubated for 24 hours in a 37° C., 5% CO₂ incubator. After 24 hours ofincubation, low serum media was replaced with 80 μL of complete medium(F12K+10% FBS) and 10 μL (10× concentration) of compounds were added andincubated at 37° C. for 30 minutes followed by stimulation of 10 μL (10×concentration) of IL-1b (Final concentration 0.25 ng/mL) overnight in a37° C., 5% CO₂ incubator. After 24 hours of incubation, the supernatantwas collected and the PGE₂ level was detected by using Cisbio HTRF kit(Catalog #62P2APEH). Briefly, 5 μL of sample (100-Fold diluted) wasdispensed into each sample well. 5 μL of each Prostaglandin E2 standard(Std 0-Std 7) was dispensed into each standard well. 2.5 μL ofProstaglandin E2-d2 working solution was added to all wells exceptnegative controls and 2.5 μL of Anti-Prostaglandin E₂-Eu3+ Cryptateworking solution was added to all wells. The plate was sealed andincubated for 5 hours at room temperature. After 5 hours of incubation,the plate sealer was removed and the plate was read on a HTRF®compatible reader. Delta F and PGE₂ level were calculated as per kitinstructions. % Fold change was calculated with respect to DMSO controlwells.

The cell-based assay was considered a positive response when treatedcells had >1.5-fold the level of PGE₂ in the vehicle treated cells whennormalized as described above. Selected compounds which had >1.5 foldinduction of PGE₂ over the positive control when tested at 1 μM includeMF-DH-455, MF-DH-343, MF-DH-458, MF-DH-519, MF-DH-459, MF-DH-319,MF-DH-516, MF-DH-296, MF-DH-456, MF-DH-520, MF-PGDH-068, MF-DH-357,MF-DH-485, MF-DH-380, MF-PGDH-070, MF-DH-368, MF-DH-135, MF-DH-472,MF-DH-469, MF-DH-393, MF-DH-419, MF-DH-301, MF-DH-517, MF-PGDH-062,MF-DH-518, MF-DH-358, MF-DH-300, MF-DH-387, MF-DH-522, MF-DH-342,MF-DH-384, MF-DH-275, MF-DH-473, MF-PGDH-071, MF-DH-404, MF-DH-482,MF-PGDH-004, MF-DH-470, MF-DH-295, MF-DH-369, MF-DH-413, MF-DH-424,MF-DH-307, MF-PGDH-008, MF-DH-406, MF-DH-403, MF-DH-418, MF-DH-297,MF-PGDH-076, MF-DH-239, MF-PGDH-006, MF-DH-471, MF-DH-298, MF-DH-521,MF-DH-345, MF-PGDH-035, MF-DH-336, MF-DH-400, MF-DH-361, MF-DH-514,MF-DH-394, MF-DH-299, MF-DH-242, MF-DH-407, MF-DH-396, MF-DH-481,MF-DH-434, MF-DH-359, MF-DH-243, MF-DH-542, MF-DH-430, MF-DH-444,MF-DH-448, MF-DH-422, MF-DH-367, MF-DH-409, MF-DH-157, MF-DH-370,MF-DH-451, MF-DH-405, MF-DH-495, MF-DH-478, and MF-DH-355.

As an example, data for MF-DH-191, MF-DH-342, MF-DH-357, and MF-DH-358are shown in FIG. 1 ; MF-DH-342, MF-DH-357, and MF-DH-358 displayedactivity in this assay.

What is claimed is:
 1. A method of treating muscle disorder, muscleinjury or muscle atrophy in a patient in need thereof, the methodcomprising administering to the patient a compound having the structureof Formula IIq:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom C₆₋₁₀aryl and 5- to 10-membered heteroaryl; wherein said aryl orheteroaryl is optionally substituted with 1 to 3 substituents eachindependently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷,—NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,and 5- to 10-membered heteroaryl; R² is H and R³ is —CF₃; or R² and R³are taken together to form oxo; each R⁴ is independently selected fromhalo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl; or two R⁴'s are taken together with the carbonatoms to which they are attached and any intervening atoms to form aC₃₋₁₀cycloalkyl, and any remaining R⁴'s are independently selected fromhalo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹,—SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to10-membered heteroaryl; each R⁵ is selected from halo, —NR⁶R⁷, —OR⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷, —NR¹⁰C(O)R⁸,—NR¹⁰SO₂R⁸, C₁₋₆alkyl, and C₁₋₆haloalkyl; R⁶ and R⁷ are independentlyselected at each occurrence from H, C₁₋₆alkyl, C₁₋₆haloalkyl, andC₃₋₁₀cycloalkyl; each R⁸ is independently selected from H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl; each R⁹ is independently selected from C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, and 5- to 10-memberedheteroaryl; each R¹⁰ is independently selected from H, C₁₋₆alkyl,C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or
 3. 2. The method of claim1, wherein the administration enables muscle regeneration and musclerepair after injury.
 3. The method of claim 1, wherein the muscledisorder is Duchenne muscular dystrophy (DMD), Becker musculardystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdlemuscular dystrophy, congenital muscular dystrophy, facioscapulohumeralmuscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), distalmuscular dystrophy (DD), an inherited myopathy, myotonic musculardystrophy (MDD), oculopharyngeal muscular dystrophy, distal musculardystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita,mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis(MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis,cancer cachexia, AIDS cachexia, stress induced urinary incontinence,urethral sphincter deficiency, or sarcopenia.
 4. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R² and R³ aretaken together to form oxo.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is H and R³ is—CF₃.
 6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R⁴ is independently selected from halo, —NR⁶R⁷,—OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.
 7. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein each R⁴ is halo. 8.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein two R⁴s are taken together with the carbon atoms to which theyare attached and any intervening atoms to form a C₃₋₁₀cycloalkyl, andany remaining R⁴'s are each independently selected from halo, —NR⁶R⁷,—OR⁸, —C(O)R⁸, —C(O)OR⁸, and —C(O)NR⁶R⁷.
 9. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein m is 0, 1, or
 2. 10.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein n is 2 or
 3. 11. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R⁵ is selected from halo, —NR⁶R⁷,—OR⁸, C₁₋₆alkyl, and C₁₋₆haloalkyl.
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein p is
 0. 13. Thecompound of claim 1, wherein R¹ is selected from C₆₋₁₀aryl and 5- to10-membered heteroaryl; wherein said aryl or heteroaryl is optionallysubstituted with 1 to 3 substituents independently selected from halo,—NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and 5- to10-membered heteroaryl.
 14. The compound of claim 13, or apharmaceutically acceptable salt thereof, wherein R¹ is selected fromC₆₋₁₀aryl and 5- to 10-membered heteroaryl; wherein said aryl orheteroaryl is optionally substituted with 1 to 3 substituents eachindependently selected from halo, —NR⁶R⁷, —OR⁸, —C(O)R⁸, —C(O)OR⁸, and—C(O)NR⁶R⁷.
 15. The compound of claim 13, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is C₆₋₁₀aryl.
 16. The compound ofclaim 15, or a pharmaceutically acceptable salt thereof, wherein thearyl is phenyl.
 17. The compound of claim 13, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is 5- to 10-membered heteroaryl. 18.The compound of claim 17, or a pharmaceutically acceptable salt thereof,wherein the heteroaryl is selected from isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiazolyl,thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.
 19. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: R¹ is selected from C₆₋₁₀aryl and 5- to 10-membered heteroaryl,substituted with a substituent independently selected from halo, —NR⁶R⁷,—OR⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁶R⁷, —SOR⁹, —SO₂R⁹, —SO₂NR⁶R⁷,—NR¹⁰C(O)R⁸, —NR¹⁰C(O)NR⁶R⁷, —NR¹⁰SO₂R⁸, —NR¹⁰SO₂NR⁶R⁷, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, and 5- to 10-membered heteroaryl; R² andR³ are taken together to form oxo; each R⁴ is independently selectedfrom halo, C₁₋₆alkyl, and C₁₋₆haloalkyl; and n is 3, m is 0, 1, or 2,and p is
 0. 20. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from the groupconsisting of: